Standards 2016 - UK Thalassaemia Society

Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK 3rd Edition, 2016

Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK, 3 rd Edition

Table of Contents Preface to the 3rd Edition............................................................................................................................... 3 Foreword to the 3rd edition.......................................................................................................................... 6 Summary of Standards.................................................................................................................................. 8 Introduction........................................................................................................................................................ 15 1: Context, and Aims of This Document.................................................................................................. 16 2: Thalassaemia – Clinical Features and Treatment..............................................................................20 Section A: Organisation of Thalassaemia Services...................................................................................23 3: Networks for Care and Commissioning.............................................................................................. 24 4: Annual Review at Specialist Haemoglobinopathy Centre.............................................................31 5: Quality Assessments................................................................................................................................ 34 Section B: Core Management Standards.................................................................................................... 38 6: Psychosocial Issues in Thalassaemia.................................................................................................... 39 7: Initial Management of the Newly Diagnosed Infant.......................................................................43 8: Decision to Start Regular Transfusion................................................................................................. 46 9: Red Cell Transfusion................................................................................................................................ 48 10: Monitoring and Management of Iron Load.................................................................................... 52 11: Referral for Blood and Marrow Transplantation............................................................................73 12: Growth, Development and Endocrine Function............................................................................77 13: Transition from Paediatric to Adult Services...................................................................................81 14: Fertility and Management of Pregnancy.........................................................................................85 15: Acute Clinical Presentation................................................................................................................. 90 16: Management of Surgery...................................................................................................................... 97 Section C: Prevention and Management of Complications................................................................101 17: Management of the Cardiovascular System.................................................................................102 18: Management of Impaired Glucose Tolerance and Diabetes Mellitus....................................113 19: Management of Bone Problems...................................................................................................... 117 20: Management of Liver Problems...................................................................................................... 121 21: Management of Dental Problems................................................................................................... 125 22: Patients Previously Treated Outside the UK.................................................................................. 129 23: Prevention Using Prenatal Diagnosis and Preimplanation Genetic Diagnosis.....................132 Section D: Non-Transfusion-Dependent Thalassaemias......................................................................137 24: Management of Non-Transfusion-Dependent Thalassaemias................................................138 Section E: References..................................................................................................................................... 145 Appendices....................................................................................................................................................... 158 Appendix A: Summary Guide to Routine Investigations..................................................................159 Appendix B: Glossary................................................................................................................................. 165

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Preface to the 3 Edition rd

About this Publication Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK, 3rd Edition (2016) ISBN (print edition): 978-1-900254-20-5 © United Kingdom Thalassaemia Society 2016 This and previous editions of the Standards are also available online at standards.ukts.org

Editorial/Writing Group •

Dr Anne Yardumian MD FRCP FRCPath, Consultant Haematologist, North Middlesex University Hospital, London and Chair of the UK Forum on Haemoglobin Disorders (Chair of Editorial/Writing Group)

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Dr Paul Telfer MA DM BM BCh FRCP FRCPath, Senior Lecturer in Haematology, Queen Mary University of London, Consultant Haematologist Bart's Health NHS Trust

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Dr Farrukh Shah MBBS FRCP FRCPath MD, Consultant Haematologist, Whittington Hospital, London and King Khalid University Hospital, Riyadh, KSA

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Dr Kate Ryan MD FRCP FRCPath, Consultant Haematologist, Manchester Royal Infirmary and Chair of the Clinical Reference Group for Haemoglobinopathies

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Dr Matthew W Darlison BA MA PhD, Teaching and Learning Technologist and Informatics lead, WHO Collaborating Centre for Community Genetics, University College London Centre for Health Informatics and Multiprofessional Education, London

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Elaine Miller BA, National Coordinator, UK Thalassaemia Society

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George Constantinou, Trustee, UK Thalassaemia Society

Grateful thanks to the following, who authored or co-authored individual chapters: •

Dr Amna Abdel-Gadir BSc MBBS MRCP, Cardiology Research Fellow, University College London Hospitals NHS Trust

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Dr Scott Akker PhD FRCP, Consultant Endocrinologist, St Bartholomew’s Hospital, London

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Dr Emmanuel O Ako BSc MBBS MRCP, Cardiology Research Fellow, University College London Hospitals NHS Trust

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Dr Maria Barnard BSc MB ChB MSc FRCP, Lead Consultant in Diabetes, Consultant in Endocrinology, Consultant in General Internal Medicine, Whittington Hospital, Honorary Senior Lecturer, University College London

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Dr Judith Bubbear MD FRCP, Consultant Rheumatologist, Whipps Cross University Hospital, London

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Dr Helen DeMarco, Lead Clinical and Health Psychologist, Red Cell Haematology Service, University College London Hospitals NHS Foundation Trust

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Dr Josu de la Fuente PhD FRCP FRCPI FRCPCH FRCPath, Consultant Paediatric Haematologist and Director Blood and Marrow Transplant Programme, Division of Paediatrics, St. Mary's Hospital London

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Dr Jo Howard, MRCP MRCPath, Consultant Haematologist and Clinical Lead /Honorary Reader in Haemoglobinopathies Guy's and St Thomas' Hospital London

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Dr Navdeep Kumar BDS FDSRCS(Eng) PhD Cert RDP, Cert Surg and Pros Implantology, Consultant in Special Care Dentistry/Honorary Lecturer University College London, Clinical Lead for Oral Medicine, Facial Pain and Special Care Dentistry, Eastman Dental Hospital for Oral Healthcare Sciences, London

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Dr Sarah Lawson BSc MB ChB MRCP FRCPath, Consultant Paediatric Haematologist, Birmingham Children’s Hospital

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Mr Gidon Lieberman BSc MBChB MD MRCOG, Consultant Gynaecologist, Whittington Health, London

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Dr Gail Miflin MA MB:BChir FRCP FRCPath, Associate Medical Director, NHS Blood and Transplant

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Dr Mary Petrou BSc PhD FRCPath, Honorary Senior Lecturer, Institute of Women's Health, University College London and Consultant Clinical Molecular Geneticist, University College London Hospitals NHS Foundation Trust

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Dr Marilyn Roberts-Harewood MRCPCH FRCPath Consultant Haematologist and Paediatric Haematologist North Middlesex University Hospital, London

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Professor William Rosenberg MA MBBS DPhil FRCP, Professor of Hepatology, University College London

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Dr Ploutarchos Tzoulis MD MSc MRCP, Consultant Physician in Endocrinology and Diabetes, Whittington Hospital and University College London Medical School

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Dr J Malcolm Walker BSc MBChB MD FRCP, Consultant Cardiologist University College London Hospitals NHS Trust; Founder and Clinical Director Hatter Cardiovascular Institute University College London Hospitals NHS Foundation Trust

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Dr Christine Wright FRCP, FRCPath, Consultant Haematologist, Sickle Cell and Thalassaemia Centre, SWBH NHS Trust Birmingham

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Acknowledgements We are grateful to the following individuals, who gave helpful comments on chapters in the draft document: •

Professor Yesim Aydinok, Professor of Paediatric Haematology, Ege University Hospital, Izmir, Turkey

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Professor Caterina Borgna-Pignatti, Professor and Chief of Paediatrics, University of Ferrara, Italy

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Dr Banu Kaya, Consultant Haematologist, Bart’s Health NHS Trust, London

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Mrs Karen Madgwick, Transfusion Practitioner, North Middlesex University Hospital, London

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Dr Sara Trompeter, Consultant Haematologist and Paediatric Haematologist, University College Hospital London and Consultant in Transfusion for Haemoglobinopathies, NHS Blood and Transplant

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Miss Susan M Tuck, Consultant Gynaecologist, Royal Free Hospital, London

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Dr Richard Ward, Director, Haemoglobinopathy Programme, Toronto General Hospital and University of Toronto, Canada

Production The publication of this book is an initiative of the UK Thalassaemia Society and the UK Forum for Haemoglobin Disorders. All the writers and editors donated their time and expertise and received no remuneration or benefits in kind for their contributions. No support, financial or otherwise, was received from the pharmaceutical industry towards the production of this book. The costs of production and publication were borne entirely by the UK Thalassemia Society.

Clinical disclaimer The content of the document is evidence based, as far as available evidence allows, and reflects the experience and opinions of its authors. However they, the UK Thalassaemia Society, and the UK Forum on Haemoglobin Disorders can take no responsibility for clinical problems arising in individual patients managed in line with the contents.

The United Kingdom Thalassaemia Society (UKTS) UK Registered Charity No. 275107

The UKTS can be contacted at: 19 The Broadway Southgate London N14 6PH Telephone: +44 (0)20 8882 0011 Email: [email protected] Web: www.ukts.org

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Foreword to the 3 edition rd

From the Department of Health I am really pleased to see an update of the standards for the delivery of care to patients with thalassaemia and I strongly support it. The document has benefited from the involvement of patients in the development and the process of implementation. Empowerment of patients and the public is an essential aim of the NHS and the thalassaemia community should be proud of their leadership role in this. Clinicians embracing these standards will see improvements in their services and the Peer Review process is also key. This document should be an invaluable source of information to commissioners when developing future services for patients. Well done to the Editor and authors. This is an important piece of work.

Professor Dame Sally C Davies FRS FmedSci Chief Medical Officer for England

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From the UK Thalassaemia Society I am honoured and delighted to be writing this foreword to the 3rd edition of the Standards. When the second edition was published in 2008, as an ordinary member of UKTS I had no idea of the tremendous amount of work which goes into producing a book of this kind. Now that it has been my privilege to be President of the Society since 2010, however, I am all too aware that it is a tremendous undertaking; which took well over a year of very hard work from all who were involved. We are extremely grateful to all the authors who contributed their time and expertise, on an entirely voluntary basis; with particular thanks of course to the Editor Dr Anne Yardumian, who has given up most of her annual leave and rare leisure hours to this project for the first half of 2016. Thanks also to our National Coordinator Elaine Miller, without whose dedication this book would not have reached publication. Another essential contributor was Dr Matthew Darlison, whose incomparable technical expertise has allowed us to produce both a printed book and an interactive on-line version which can be accessed via the UKTS and UKFHD websites (www.ukts.org and www.haemoglobin.org.uk). Like many of my peers who have thalassaemia, I will be requesting a copy of the book so that I can compare my own treatment with the guidelines; but I know that I am fortunate to have been treated all my life in a specialist centre. The excellent care I have enjoyed has given me access to a normal life – higher education, a career, marriage and very recently fatherhood, with the birth of my twin sons in April 2016. I am extremely thankful for all the skill and care that has kept me fit enough to enjoy these privileges. However, I am all too aware that not everyone with thalassaemia is as fortunate. In early 2016 UKTS carried out a national survey of adult thalassaemia patients; and some of the reported outcomes made rather uncomfortable reading. Despite the progress that has undoubtedly been made due to better chelation, networks for care and peer reviews of services, people living in the UK today with thalassaemia are still suffering from social stigma, discrimination and in some cases, inadequate access to specialist care. It is our job as a patient Society to try to address the medical and social barriers which keep some of those who have thalassaemia from achieving their goals. We will also continue to work with clinicians and health care planners to improve and refine the networks for care. In the UK we have some of the world’s leading authorities on thalassaemia treatment; and networks for care should mean that every individual has access to this expertise. Finally, services designed to fit around the patient’s working life are still the exception; and this needs to change if people with thalassaemia are to become fully integrated, contributing members of society. This is a goal we will continue to pursue – until health care planners recognise that we cannot become fully independent, productive people if our health care is still being delivered as though we were invalids with no commitments or responsibilities. I hope that this new edition of the Standards will be useful to all those involved in the planning and delivery of thalassaemia care; and to my fellow “patients” – I encourage you to use this book, learn about your condition, ask questions, be active and engaged in your treatment. We have set the Standards; now let’s work together to deliver them.

Gabriel Theophanous President, UK Thalassaemia Society 2016

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Summary of Standards 3: Networks for Care and Commissioning  All regions must deliver care for people with thalassaemia through a clinical network incorporating local haemoglobinopathy teams (LHT) and one or more Specialist Haemoglobinopathy Centres (SHC).  Established pathways within the network should ensure that all patients have access to an SHC – for their regular management if living nearby and for a comprehensive review of their condition and care at least once a year, at an ‘annual review visit’, if they live more distantly and receive their regular care from an LHT.  Specialist clinical advice should be available from the SHC at all times, for patients who present acutely to their local centre with complications the local team may not be experienced in managing. There should be the facility for urgent transfer of a patient to the SHC for complex care.  The network should have sufficient resources (health care professionals, management and administrative staff) to function effectively, and should develop systems for information sharing, clinical governance, accountability and staff development.  A ‘key contact’ health professional will be designated for each patient.  Patients and carers should receive regular education, supervision and support in thalassaemia care, chelation therapy and other home treatments.  All health providers within the network – primary care teams, LHTs and SHC – should record and exchange information relating to clinical events, monitoring investigations, and changes in treatment. Correspondence should always be copied to patients/carers.  Consent should be sought from all patients for entry of their details on the National Haemoglobinopathy Registry, and data entered in a timely fashion to assist audit and assessment of good quality outcome information.  Patients and carers should be involved in making decisions about management and delivery of care.  Patients and carers should have access to peer support groups.

4: Annual Review at Specialist Haemoglobinopathy Centre  Every person with thalassaemia will have the opportunity for their care and condition to be reviewed at least annually with a team of health care professionals who have particular experience in caring for thalassaemia disorders. This can take place during a visit to the Specialist Centre, or at an outreach clinic where members of the Specialist Team visit the local centre at which the person receives their routine care.  The assessment should cover all aspects of care including educational and lifestyle factors that may affect health or influence adherence to treatment.  Discussion of treatment options should include any new information which has become available, and an individual treatment plan for the next 12 months will be agreed.  A copy of the annual review consultation including the care plan will be copied to the patient or, for children, their parents as well as health professionals involved in their care.  Data should be entered into the annual review screens of the NHR for consented patients.  People in families affected by thalassaemia should be able to meet and gain support from other affected families at the Centre or in the community.

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5: Quality Assessments  An independent external peer review of thalassaemia services should be completed every twothree years.  Results from this should be made available to the inspected services, to NHS Commissioners and NHS England.  Commissioners should designate clinical networks, support the establishment and ongoing running of the networks and review outcome data from the network at least annually.  Specialist haemoglobinopathy centres should have fail-safe mechanisms for enrolling all newborns with thalassaemia into clinical care.  Specialist and local haemoglobinopathy centres should have enough medical and nursing time to care for patients with thalassaemia, and experienced support staff, aware of the issues facing patients with thalassaemias.  There should be a clear process for transition from paediatric to adult care.  There should be access to appropriate out of hours services.  Adequate information should be provided for patients, and readily available comprehensive clinical guidelines for staff.

6: Psychosocial Issues in Thalassaemia  Consideration of the psychosocial demands and support needs of living with thalassaemia is a key role and responsibility for all professionals involved in the provision of care for people with this condition.  Consideration of the family context and developmental/life stage of the person with thalassaemia is key to ensuring that care and treatment recommendations are individually tailored and appropriate for each patient.  Psychosocial support alongside specialist psychological care should be provided as a standard part of thalassaemia clinical care, in both paediatric and adult services.  Core staffing of Specialist Haemoglobinopathy Centres should include a clinical psychologist with a special interest and experience in thalassaemia.

7: Initial Management of the Newly Diagnosed Infant  Diagnosis of a child with a serious thalassaemia syndrome will be timely and accurate. It should be established as soon as possible after birth, and should include globin genotype.  The neonatal heel prick test is a screening, not diagnostic, test and early confirmation is required.  The child must be monitored closely to determine the likely clinical course.  The family should be informed fully and sensitively from the outset once the diagnosis is confirmed, by appropriately experienced professionals, with the use of a culturally-appropriate health advocate if necessary, and with the opportunity for full discussion. Suitable written information should be given to them.  A management plan tailored to the individual child must be agreed and implemented.  The family will meet their ‘key contact’ within the clinical team, and given contact numbers for subsequent use.  The family should be informed about the National Haemoglobinopathy Registry and asked to give consent for the child's details to be recorded on it.  The family should be given the contact details for the UK Thalassaemia Society and any local support group.

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8: Decision to Start Regular Transfusion  Infants with β thalassaemia will be monitored carefully for clinical signs indicative of the need for transfusion. Transfusion will be started promptly when there is clinical evidence of severe anaemia, failure to thrive and/or thalassaemic bone deformity.  Infants and children with a milder ‘thalassaemia intermedia’ phenotype will be identified clinically and not subjected to regular transfusion inappropriately.  Extended red cell phenotype and genotype should be performed before starting regular transfusions to ensure compatible blood is transfused and to reduce the risk of alloimmunisation.  Before a first transfusion, a course of hepatitis B vaccinations should be started, and completed if possible.

9: Red Cell Transfusion  Trough haemoglobin levels should be maintained ~ 90-105g/l.  Blood must be ABO compatible and antigen negative for any clinically significant antibodies the patient is known to have, or to have had previously identified even if not currently detectable. It should be fully matched for all the Rh antigens and K.  Units should be less than 2 weeks old and, in adults, of larger volume where possible.  There should be a clear record of patient’s transfusion requirements outlining volume, frequency and target haemoglobin.  Transfusions will be given on each occasion in a designated age-appropriate area with suitable facilities, experienced regular named nurses and familiar supervising medical team.  Cannulation will be undertaken by an experienced nurse, doctor or phlebotomist.  Pre-arranged transfusions should be started within 30 minutes of the patient’s arrival.  Good transfusion practice must be observed.

10: Monitoring and Management of Iron Load  A protocol for iron chelation therapy in children and adults should be shared between the Specialist Haemoglobinopathy Centre and Local Hospital Teams within the clinical network, and reviewed at regular intervals. This should be based on current published evidence, expert opinion, and national specialist commissioning guidance.  Decisions about initiating and changing chelation therapy should be made by the thalassaemia specialist, taking into account the preferences of the patient and carers, and the views of other involved health care workers.  Patients and carers should be informed about benefits and possible adverse effects of each option and offered information in formats appropriate for age, language and literacy, with health advocacy as needed. The decision process should be recorded in the patient's records.  Patients and carers should be supported in adhering to chelation therapy using a multidisciplinary team approach including clinic doctors, nurse specialists, clinical psychologists, and play therapists for children. Peer support should be encouraged.  Adherence should be monitored regularly, and problems carefully identified and addressed in a non-judgmental manner.  All patients should have access to Cardiac MRI for assessment of myocardial iron overload and cardiac function, and to liver MRI for assessment of liver iron concentration. The MRI methodology should be standardised and validated.  Patients should be carefully monitored for side effects of iron chelation therapy, and treatment interrupted or reduced promptly to avoid serious toxicity.  The outcomes of chelation therapy within local clinics and the clinical haemoglobinopathy network should be audited regularly.

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11: Referral for Blood and Marrow Transplantation  The families of all children with thalassaemia should have the opportunity to discuss the option of BMT with the team at a transplant centre with experience in undertaking the procedure for this indication, whether or not there is currently a matched sibling donor.  They will be fully informed about all the potential risks and benefits of the procedure, in the immediate, middle and long term.  For those with an appropriate donor who choose to proceed with transplant, it must be undertaken at a centre with specific experience and expertise of managing thalassaemia transplants.

12: Growth, Development and Endocrine Function  Iron loading should be kept to a minimum, by careful monitoring and the use of effective chelation treatment, to reduce the risks of endocrine damage.  Paediatric and adult specialists in bone metabolism and endocrinology, with interest and expertise in managing the particular complications encountered, should be involved in the care of children and adults with thalassaemia, ideally in a joint clinic setting.  Children should have growth and development monitored regularly from diagnosis until they have achieved full sexual maturity and final adult height. Any change in expected growth and development should be identified, investigated and treated promptly.  Where paediatric endocrine input has been necessary then careful transition plans should be made at completion of puberty and linear growth. Ideally such transition should take place in a combined clinic. A detailed clinical summary and discussion should take place to ensure there is no disruption to treatment at this critical stage of adolescence.  Adults and children should be routinely assessed, at least annually, for evidence of disturbance of the hypothalamo-pituitary axis, for calcium and bone homeostasis, and thyroid function.

13: Transition from Paediatric to Adult Services  Support and education will be given to the young person and their parents or carers over time to nurture independent, informed young people who can take responsibility for their health and choices.  Each young person requires a named/key worker for transition and the transition process should commence by 13 years of age.  Adult and paediatric teams will work collaboratively with the young person and their parents or carers to provide a timely and smooth hand-over. Primary, secondary and tertiary health care providers and community teams should be involved in the process, and in the young person’s ongoing care.  Any anxieties that the young person and their parent(s) or carer(s) may have, arising from the change from paediatric to adult health providers, will be addressed.  Psychosocial stresses that may negatively impact on adherence with their transfusion regime, medication and/or and self-care will be identified and managed.  Close monitoring of thalassaemia treatment should continue over the transition period, with particular attention to monitoring of iron stores and adherence to iron chelation therapy.

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14: Fertility and Management of Pregnancy  Each Specialist Centre will identify a paediatric endocrinologist with experience in the management of thalassaemia.  Pubertal development, growth, and endocrine function will be closely monitored in boys and girls with thalassaemia, and prompt referral made if there is any suspicion of problems.  Women contemplating pregnancy will be assessed for possible risks to themselves and their babies and this evaluation up-dated as needed.  At any time when the patient wishes she/ he should be referred to a fertility / endocrine / assisted conception clinic with experience of thalassemia patients, to allow discussion about treatment options; culturally appropriate advocacy will inform these discussions.  Women will be jointly managed during pregnancy and delivery by a 'maternal medicine' obstetrician experienced with haemoglobin disorders, and by their haematologist.

15: Acute Clinical Presentation  Specialist Haemoglobinopathy Centre teams will offer education about thalassaemia-specific acute presentations to patients and health professionals across the network, including Emergency Department and Primary Care colleagues, with details of how to access specialist advice.  Specialist haemoglobinopathy teams will make clear to their patients and to acute medical services at the local and specialist hospitals how they can be contacted for urgent clinical advice.  Patients presenting with acute clinical problems will be assessed with consideration given to the range of thalassaemia-specific complications they might develop.  If staff with appropriate knowledge and experience are not available on site, there must be urgent consultation with the specialist centre, and referral on after stabilisation where necessary.  Appropriate management should be instituted as quickly as possible.

16: Management of Surgery  Patients should be carefully assessed pre operatively with specific reference to complications relating to thalassaemia including cardiac, thrombotic, endocrine and metabolic disturbances.  There should be close liaison between the surgical, anaesthetic, and paediatric/haematology teams in planning surgery, and shared care arrangements should be agreed prior to a surgical admission.  Patients undergoing urgent surgery should always be discussed with the SHC team, during preparations for theatre.  Patients should have been given adequate information regarding thalassaemia-specific and other issues related to surgery to allow informed consent.

17: Management of the Cardiovascular System  Every patient must have access to a cardiology service with experience in the management of cardiac consequences of thalassaemia.  Children should be referred for their first cardiac evaluation, including clinical assessment, ECG, echocardiogram and MR T2* between the ages of 7 – 10 years.  Cardiology assessments thereafter should be at intervals guided by symptoms, adequacy of chelation and findings of previous assessments.  A high risk time for development of cardiac problems is 16-25 years of age, and during this period assessments should be undertaken at least yearly.  Patients with myocardial iron and left ventricular (LV) impairment with new-onset symptoms must be discussed with the SHC team, and reviewed urgently for consideration of inpatient intensive chelation.

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 Patients must be considered for anticoagulation if they have indwelling venous lines, or atrial fibrillation, including paroxysmal AF.

18: Management of Impaired Glucose Tolerance and Diabetes Mellitus  A paediatric and adult consultant diabetologist should be identified for each Specialist Haemoglobinopathy Centre.  Patients should be checked annually for impaired glucose regulation and diabetes from puberty, or from age of 10 years if there is a family history of diabetes.  Patients with diabetes should have a full annual diabetes review, including glycaemic control, cardiovascular risk factors, diabetic complications and sexual health.  Patients with diabetes should have access to a clinical health psychologist with experience in diabetes management.

19: Management of Bone Problems  Transfusion therapy will be initiated in time to prevent irreversible deformities associated with bone marrow expansion.  Doses of desferrioxamine will be kept in the range to minimise the risk of bone toxicity or reduce height velocity. Any bone changes possibly related to deferrioxamine toxicity should be suspected and investigated in children with bone/joint pain or short stature.  Management of the maturing skeleton should focus on achieving peak bone mass.  All patients should have vitamin D measured with supplements given if needed.  All patients should be advised of the need for adequate dietary calcium for healthy bones.  All patients should be advised on lifestyle changes that promote achieving peak bone mass and maintaining bone mineral density, BMD: smoking cessation, avoiding excessive alcohol consumption and undertaking weight bearing exercise.  Diagnosis of hypogonadism and other endocrinopathies should be prompt, and appropriate hormone replacement therapy given.  Adult patients should be monitored for low bone mass/osteoporosis.  Bisphosphonates and other bone specific agents should be considered in patients with deteriorating BMD/osteoporosis confirmed on DXA bone mineral density scanning, particularly if there have been fractures.  Osteoporosis treatments should be regularly reviewed.  If there is chronic severe bone pain, not amenable to corrective treatment, a patient should be managed together with a specialist pain team.

20: Management of Liver Problems  Liver function tests should be monitored at regular monthly intervals.  Liver iron levels should be maintained within safe limits to avoid hepatic damage, using the range of available chelation options and taking steps to encourage adherence to treatment.  Adjustments to chelation and other treatment should be made promptly if abnormalities of liver function are detected on routine monitoring tests.  Vaccination against hepatitis A and B virus infection should be ensured.  Liver disease should be managed jointly with a designated specialist hepatologist.  Management of chronic hepatitis C virus infection should include histological assessment of fibrosis on biopsy and/or non-invasive techniques.  Antiviral therapy aimed at sustained viral clearance should be planned and managed in collaboration with a designated specialist hepatologist.  Patients with established cirrhosis should have regular surveillance checks for hepatocellular cancer. 2016

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21: Management of Dental Problems  Adequate red cell transfusion in children with thalassaemia should be sufficient to prevent the development of marrow overgrowth and facial bone changes, and some of the associated dental problems.  All patients should access regular dental care to prevent oral infection and manage the potential orofacial features of thalassaemia.  Patients presenting with acute dental infections/abscesses should receive urgent dental care and antimicrobial therapy as required.  Close liaison with the haematology team is required to determine the potential complications when delivering invasive dental treatment, and to put measures in place to reduce risk.  All patients should ideally have a comprehensive dental assessment with their local dentist prior to the commencement of bisphosphonate therapy to ensure that they are as dentally fit as feasible.

22: Patients Previously Treated Outside the UK  Children and adults who have been receiving treatment outside the UK will be seen, as soon as possible after they arrive, at an established Specialist Haemoglobinopathy Centre for a thorough assessment.  Transfusion treatment will be re-started without delay.  Any complications which may have developed will be detected and discussed with the individual and family and management plans put in place.

23: Prevention Using Prenatal Diagnosis and Preimplanation Genetic Diagnosis  All couples at risk of having children with a thalassaemia disorder should be referred to specialist genetic counselling as soon as the risk is recognised.  Counselling is provided by a genetic specialist with specific experience in both prenatal diagnosis and preimplantation genetic diagnosis for haemoglobin disorders.  DNA analysis is provided for all at risk couples.  All at risk couples are informed of prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) as options to achieve a healthy family.  A couple at risk of having a child with a thalassaemia disorder should be offered PGD if the female partner is under 40 years of age at the time of treatment, and there is no living unaffected child from the current relationship.  If the woman has a thalassaemia disorder, her treating haematologist should be involved in the management plan prior to PGD.

24: Management of Non-Transfusion-Dependent Thalassaemias  A comprehensive DNA diagnosis (β globin mutations, α globin genotype, Xmn1 C→T polymorphism) should be undertaken as soon as the diagnosis of thalassaemia has been established.  Parents, carers, and patients should be counselled at diagnosis, and as often as needed thereafter, about the likely course of the condition and therapeutic options available.  During the first 3-5 years of life, children with thalassaemia should be monitored carefully and systematically for evidence of thalassaemic features which may require regular transfusion therapy. Older children, adolescents and adults with a diagnosis of NTDT should continue to be monitored regularly, for consideration of indications for transfusion, and for iron loading, pulmonary hypertension, and extramedullary haematopoietic masses in particular.  Complications of NTDT should be identified at an early stage and treated promptly.

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Introduction

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1: Context, and Aims of This Document “Having access to out of hours transfusion has allowed me to achieve success academically and professionally, which means I pay more tax and live a normal life.” “Thalassaemia has never affected my education/career but I have never been able to build a relationship. My family think I am too ill.” “Thalassaemia has never hindered me doing the things I want to do, it has only limited the amount on occasions.”

Thalassaemia in the UK Modern treatment of thalassaemia in the UK is for the most part a success story. Children born in the UK today with thalassaemia are expected to survive to adult life in good health, to lead essentially normal lives in respect of career and family; and to live a normal or near normal lifespan. Unfortunately, this outcome is still not universal throughout the UK. Premature deaths still occasionally occur and children still develop complications such as growth failure and hypogonadism due to endocrine damage. These complications are related to transfusional iron overload and the ability to adhere to iron chelation therapy (Modell and Berdoukas 1984; Olivieri et al. 1994; Brittenham et al. 1994). Despite strenuous efforts by clinicians to develop networks for care, in order that all patients can access highly specialist care as needed, in 2016 outcomes and experience remain consistently better in a some areas than in the UK as a whole (Modell et al 2000; Porter and Davis 2002; WMQRS Review of Services for Haemoglobin Disorders for Children 2010-2011, WMQRS 2013). Many thalassaemia patients in the UK are still managed in clinics of less than 10 patients (Modell et al. 2001; WMQRS 2011; WMQRS 2013), reflecting the patchy distribution of patients. Outside the North West of England, the West Midlands and some London areas, the majority of centres providing specialist care for haemoglobinopathy patients have a relatively small number of thalassaemia patients alongside a much larger population of sickle cell patients. Hence the number of centres which can realistically be regarded as providing specialist care for thalassaemia are few and far between. Further work is needed to ensure that the original aim of the first edition of the Standards (2005) is met – namely, that every patient, regardless of location, should have access to optimal, specialist management guidance and supervision, as well as local routine care.

Improving thalassaemia care There have been a number of significant developments since the 2nd edition of the Standards in 2008. A National Haemoglobinopathy Registry was launched in 2008, with the aim of informing commissioning and healthcare planning by collecting information regarding numbers of affected people looked after at the various centres, and recording aspects of their clinical care and outcomes. Additionally, in 2010 the National Haemoglobinopathies Project produced a report on commissioning specialist haemoglobinopathy care; and an All Party Parliamentary

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Group for Sickle Cell and Thalassaemia has been established, currently chaired by Diane Abbott MP. A Clinical Reference Group (CRG) for haemoglobinopathies which includes clinicians, commissioners, public health experts and service users was set up under the auspices of the National Programme of Care for Blood and Infection to advise NHS England on the best way these specialised services should be commissioned and provided. The CRG prepared the service specifications Specialised Services for Haemoglobinopathy Care (All Ages) (NHS England 2013) and has recently developed a clinical commissioning policy proposal for the treatment of iron overload in patients with chronic inherited anaemias, including the thalassaemias. The policy proposes that monotherapy with each of the three licensed iron chelator drugs – desferrioxamine, deferiprone and deferasirox, and the most frequently used combination of desferrioxamine with deferiprone, should be routinely commissioned for patients. It emphasises that MRI scans to quantitate tissue iron should be available for monitoring, that oversight of iron chelation should be undertaken by experienced clinicians at a Specialist Haemoglobinopathy Centre, and that decisions should take into account the clinical circumstances together with the views of the patients and carers. This policy is under consideration by the Clinical Priority Action Group (CPAG) and a decision is expected in summer 2016. The NHS Screening Programme for Sickle Cell and Thalassaemia has been fully rolled out throughout England (2009); and Wales and Scotland have set up their own screening programmes. It should be noted however that some of the aims of the Screening Programme , which included early diagnosis of carrier couples and timely offer of prenatal diagnosis, have proved challenging; with only 40% of PND tests being carried out by 12+6 weeks gestation in 2014/15 (Public Health England 2014a). Work to address the complex issues surrounding the late detection of couples at risk is ongoing. Births of babies affected by clinically significant thalassaemias have remained consistent at between 20 – 30 affected births per annum(Public Health England 2014) A positive development from the work of the NHS Sickle Cell and Thalassaemia Screening Programme and the Newborn Outcomes Information Governance and Clinical Group has been the successful pathway into care for affected babies. Even though the detection of clinically significant thalassaemia is not a primary aim of the newborn screening programme, 99% of screen positive babies (both sickle and probable beta thalassaemia) were referred to specialist services by 8 weeks of age (Public Health England 2014). The UK Forum for Haemoglobin Disorders, working with the West Midlands Quality Review Service (WMQRS) developed a comprehensive set of Quality Requirements drawn from the 1st edition of the Standards, and the parallel sickle cell disease care standards; and these have been used to introduce a system of ‘peer reviews’ to assess service provision across networks for care. Since 2008 three peer reviews have taken place: WMQRS Review of Services for Haemoglobin Disorders for Children 2010-2011, WMQRS Review of Services for Haemoglobin Disorders for Adults 2012-2013 and WMQRS Review of Services for Haemoglobin Disorders for Children and Adults 2014-2016. The resulting reports (WMQRS 2011; WMQRS 2013; WMQRS 2016) highlighted a number of issues, of which the most worrying is the lack of resources in terms of experienced specialist medical and nursing staff. These highly complex patients cannot be successfully managed without a holistic, individually tailored treatment regime supervised by skilled and experienced clinicians. Networks for care and annual reviews by expert clinicians should have eliminated most of the inequalities in care which existed before the publication of the first Standards in 2005; and there is no doubt that improvements have been made. The majority of patients report that they are receiving their essential monitoring tests regularly, including heart and liver MRIs, DXA scans (UKTS national survey 2016) and this is to be welcomed. However there are still areas which do not seem to be adequately covered by the network system and patients who have never had an appointment with an expert clinician. The internet and social media has opened up the world for everyone, and patients are better informed than ever before. They compare treatment and avidly research the latest developments, often becoming very knowledgeable and increasingly feeling equipped to become active participants in the management of their condition.

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Organisational aspects of thalassemia care The last ten years have seen radical changes in the treatment of thalassaemia. Since the introduction of the oral chelators deferiprone and deferasirox, the use of desferrioxamine has declined rapidly, and the fact that so many patients now use oral chelators has led to changes in how thalassaemia is perceived and experienced, for those living with the condition and for the numerous agencies involved in the management of their health and their lives. The new freedom from “the pump” has brought new responsibilities and expectations; more than ever before, people who have thalassaemia are expected to work full time to support themselves. Many do, but the services in many places have not adapted to accommodate their needs. For the most part, services are still organised on the basis that the thalassaemia patient has little else to do but attend hospital appointments. It would be worthwhile for every doctor and every nurse who looks after patients with this condition to stop and try to imagine how their own life would be if they were living with thalassaemia. Working full time, looking after a family, expected to keep performing at the same level for the entire month as the haemoglobin level gradually falls, trying not to get irritable with children, family members, colleagues – and then a nurse casually tells you your blood isn’t ready and you should come back tomorrow, when your employers are already making irritable noises about the amount of time you have to take off! A person who has thalassaemia, however well qualified, however eminent in his or her profession, however meticulously organised in life, will always be dependent on the opening times of their day unit. Some advances in treatment have led to unexpected developments. For example, before the first edition of the Standards was published in 2005, the thalassaemia community naïvely imagined that with the wide availability of oral chelators, the problem of adherence to chelation therapy would be solved finally and fully. This has not proved to be the case however, and the community has come to realise that, far from solving the issue, we have merely raised other questions about the interplay between the physical and the psychological. The international thalassaemia community faces a dichotomy between two groups of patients who are at risk of serious complications from iron overload – those who have no access to chelator medication, and those who, for poorly understood reasons, cannot take that same medicine even when it is made freely available to them, and often even delivered to their homes. In the UK we now have a cohort of beta thalassaemia major patients who are approaching their sixties. These are people who were told they would not survive beyond childhood, and who saw many of their fellow thalassaemia patients succumb to iron overload in the 1970s and 80s. Thanks to a modicum of luck and the persevering skill of a few pioneering clinicians, this lucky few remain to tell us about the days before chelation; when they were all too aware that every transfusion brought them closer to death from heart failure. They remember the dreaded, agonising “bolus” injections of desferrioxamine which were their only hope of survival, and how they welcomed the advent of the early pumps (as big as typewriters) as a less painful method of administration. The frustration of these older members of the thalassaemia community is tangible when they talk to a teenager who doesn’t take deferasirox because it tastes chalky. Thalassaemia patients in the UK for the most part ‘have never had it so good’ – with modern treatment, improvements in overall health and life expectancy, the ability to become parents, to enjoy careers and family life. The fear of early death has largely vanished; unlike their predecessors in the 1980s UKTS members do not open every newsletter to see obituaries of youngsters in their twenties. Patients no longer expect to die young, but with the decline of these fears new social concerns have arisen – peer comparison for growth and maturity, infertility, cultural problems such as being regarded as “sick” and therefore unmarriageable. Now knowing that they need not suffer an early death, people with thalassaemia quite reasonably want to live the same lives as their contemporaries, they want to look the same and act the same; and they find it harder and harder to accept any restrictions imposed by their condition. Most of these issues are beyond the scope of clinicians to resolve, but they are essential elements which contribute to the outcome of treatment for each patient. To examine all these issues we need expert psychology support and research; but the evidence from even the most recent round of peer review assessments of services is that psychology services for thalassaemia are among the most under resourced, and in many areas are practically non-existent.

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Aims and scope of these Standards In this document we have again outlined a model of care, and have defined standards for delivery of care, for patients with thalassaemia. We have addressed predominantly the needs of those who are transfusion-dependent (thalassaemia major), and, in a separate section those with non-transfusion-dependent thalassaemia, NTDT (Section D: Non-Transfusion-Dependent Thalassaemias ). It is not intended to offer full clinical guidelines as these are well covered in other available published guidance. Overall our central focus is on the way in which services are structured and delivered. In this edition, we have ordered the main chapters in line with a pathway for a person with thalassaemia, from birth into older adulthood. This works well in parts, but is to some extent artificial as many potential complications span the age ranges to varying degrees. Some chapters need therefore to be read together – for example chapters 12: Growth, Development and Endocrine Function , 18: Management of Impaired Glucose Tolerance and Diabetes Mellitus , and 19: Management of Bone Problems . Growth, development and endocrine function, as well as fertility issues, are now included in the ‘Core Standards’ section, in recognition of the importance of these aspects of care for patients and their families. A chapter on Quality Assessments, peer review, has been added to Section A: Organisation of Thalassaemia Services and a number of new clinical chapters have been introduced: 18: Management of Impaired Glucose Tolerance and Diabetes Mellitus , 21: Management of Dental Problems, and 23: Prevention Using Prenatal Diagnosis and Preimplanation Genetic Diagnosis. Appreciating the central role of the UK Thalassaemia Society in planning and implementing changes, we have as before included at the start of each section, a number of relevant quotations, derived largely from the 2016 national survey of adult patients organised by UKTS. We hope that these enliven the text, as well as giving insight into how patients experience their condition and prioritise the issues they face. The document is aimed primarily at healthcare professionals who care for people with thalassaemia, and technical terms are mostly used without explanation in the text. However, we hope that it may also be of interest to patients and their families, and a Glossary is included (Appendix B) to help understanding of any unfamiliar terms.

Levels of evidence Apart from the chapter on monitoring and management of iron load, which is fully referenced, the content of the standards is largely practical clinical and organisational guidance, most of which is not subject to formal trials or evidence base and in most areas, as previously, we have relied largely on published retrospective analysis of clinical data and non-randomised, noncontrolled interventions, expert opinion, and the views of patients and families. For these standards we have adopted two grades of practical interventions: •

Requirements – being that which providers must do to ensure safe and adequate care: where omission could lead to poor clinical outcomes, and

•

Recommendations – being that which would be beneficial and which providers should try to do, but which would be less likely to have a direct impact on clinical outcomes.

Conclusion In summary, we feel that there is cause for real optimism in the way that services for the management of thalassaemia and sickle cell disease are developing in the UK. We trust that everyone working in thalassaemia clinics across the UK will read these standards and apply them locally. Additionally, we expect health service managers and commissioners to be fully aware of the challenges presented by managing these disorders and to work to ensure equitable, high quality care for all those affected. We hope that patients and user groups will also find the document helpful, supporting them in negotiating for the best possible care.

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2: Thalassaemia – Clinical Features and Treatment “You can never forget about thalassaemia because it’s always there in the background. You need treatment at all times.” “I feel there is always someone in a worse situation than me so I just get on with it.” “Treatment has got better over the years and I am now 51 years of age. I usually see my haematologist every 6-8 weeks and she is very supportive.”

Pathophysiology and geographical distribution Beta (β) thalassaemia is a genetic disorder of haemoglobin production. It is inherited in an autosomal recessive pattern (apart from in very rare 'dominant thalassaemia' mutations), and is common in people originating from the Mediterranean, the Middle East, South Asia, South East Asia and the 'Far East'. In the UK, β thalassaemia major is more or less restricted to ethnic minority populations, the largest groups being Cypriot, Indian, Pakistani and Bangladeshi (Modell et al. 2001). The disorder is due to a range of mutations associated with the β globin gene, resulting in reduced or absent production of β globin, one of the constituents of the adult haemoglobin molecule (HbA). Reduced β globin production, leading to excess free alpha (α) globin chains, damages red cell precursors in the bone marrow. This results in ineffective erythropoiesis, severe anaemia and compensatory erythroid marrow hyperplasia.

Classification Homozygous β thalassaemia can be broadly categorised clinically as: • β thalassaemia major (BTM or TM), in which haemoglobin production is so reduced that normal growth, development and quality of life can only be achieved by regular red cell transfusions from infancy. Death at an early age is inevitable if no transfusions are given. Where the term 'thalassaemia' is used without qualification, it usually refers to β thalassaemia major. • β thalassaemia intermedia (BTI or TI), in which a reduced amount of haemoglobin is produced, sufficient for growth and development without the absolute requirement for regular transfusions. Growth may fail, and other complications may develop in later childhood and adulthood, requiring regular transfusions. However, there is a continuum or ‘grey-scale’ of clinical severity, with no absolute cut-off between the two. The term ‘non-transfusion-dependent thalassaemia’ NTDT is now commonly used to describe those who may require occasional, but not regular transfusion, in contrast to those whose haematology, symptoms and signs have required them to be treated with regular transfusions - ‘transfusion-dependent thalassaemia’ or TDT. The compound heterozygous states of β thalassaemia with a thalassaemic haemoglobin variant (including HbE, Lepore, Knossos) or

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an alternative thalassaemic mutation (e.g. δβ thalassaemia) often result in NTDT, but can cause transfusion-dependent thalassaemia. Haemoglobin H disease is a result of deletion of three of the four α globin genes or from nondeletional mutations which inactivate them. It is usually a mild condition with features typical of a chronic haemolytic anaemia, although a few individuals develop more severe problems, including transfusion dependency. If all 4 α globin genes are affected, the result is intrauterine anaemia and usually the early stillbirth of a hydropic infant (Bart's Hydrops fetalis) as α globin chains are required for fetal haemoglobin. These standards apply chiefly to transfusion-dependent patients, and additional issues for those with non-transfusion-dependent thalassaemia are outlined in Section D: Non-TransfusionDependent Thalassaemias . In a small number of cases worldwide to date, it has proved feasible, if prenatal diagnosis establishes that a fetus has α thalassaemia major, to give intra-uterine transfusion to sustain it until birth. This treatment needs to be started early, as otherwise serious disability results. After birth, such an infant will need to continue on a regular transfusion regimen as for BTM. Separate guidelines are necessary for the antenatal management of this condition.

Haemoglobinopathy screening Population and antenatal screening to identify carriers of β thalassaemia is feasible within a health care system. Identification of a carrier parent, usually the mother, followed by testing of the partner allows identification of couples at risk of having an affected child. Having been counselled they can make informed choices about prenatal diagnosis and termination of an affected fetus. The effective delivery of this service has led to a great reduction in affected births in several countries. Systematic screening of pregnant women in England is now in place, through the NHS Sickle Cell and Thalassaemia Screening Programme for linked antenatal and newborn screening. Newborn screening is primarily aimed at detecting babies with sickle cell disease, in whom early interventions can prevent fatal complications before clinical presentation. However, most babies with β thalassaemia major will be identified by the same screening test, and early diagnosis can reduce morbidity associated with late presentation, and anxiety for affected families.

Clinical features of untreated thalassaemia Babies with homozygous β thalassaemia are initially asymptomatic, as the major haemoglobin at birth is fetal haemoglobin (HbF). As a result of the physiological switch from HbF to HbA, the latter becomes predominant by about four to six months of age, and it is from this stage onwards that infants with thalassaemia major can become symptomatic. Clinically, the presentation is insidious, with poor feeding, faltering growth, pallor, and increased susceptibility to infection. If untreated, progressive anaemia and metabolic stress eventually cause heart failure and death. There is enlargement of the liver and spleen. The ineffective expansion of the erythropoietic marrow results in bone thinning and deformity. Untreated, children with BTM die from heart failure or infection before the age of five years.

Standard treatment Standard treatment consists of regular blood transfusions given every three to four weeks. Transfusions correct the anaemia, enable growth and normal activity levels, prevent enlargement of the spleen and inhibit the erythroid marrow expansion. The most important long-term problem associated with regular transfusions in thalassaemia is iron overload. Blood contains iron which cannot be excreted from the body, and a typical thalassaemia patient on a regular transfusion programme will accumulate 0.3-0.5mg/kg of iron per day. Excessive iron is toxic, the most vulnerable organs being the heart, liver and endocrine glands. Once the body has accumulated 12-24g of iron significant clinical manifestations of iron toxicity can be expected (Gabutti and Borgna-Pignatti 1994). Without treatment to remove the iron, the majority of patients developed cardiac problems and died of heart failure by the age of 20. Therapy to

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remove or 'chelate' excess iron is therefore essential and this must be started within a year or so of starting regular transfusions. The established regime requires subcutaneous infusions of the chelating agent desferrioxamine given 5-7 nights per week over 8-12 hours. This regime can stabilise the body iron load at an acceptable level in a majority of patients, and was shown to reduce the risk of cardiac disease, and to improve survival (Modell and Berdoukas 1984; Olivieri et al. 1994; Brittenham et al. 1994). Other complications of iron overload, such as short stature and hypogonadotrophic hypogonadism may also be prevented (Olivieri 1997). The main problem has been adherence to the regular subcutaneous infusions of desferrioxamine. The infusions are time consuming to set up, and require introduction of a subcutaneous needle on each occasion followed by continued attachment to an infuser device over 8 -12 hours. They are unpopular and often resisted, especially by older children and teenagers, because they can cause local discomfort and because having to undertake this onerous self-treatment sets the child apart from his or her peers. In large, well organised thalassaemia centres, physical and psychological problems with adherence can be addressed methodically, and excellent survival was seen in younger patients (Porter and Davis 2002). In the UK as a whole, however, survival did not improve to the extent hoped 30 years ago when desferrioxamine became available, and this is probably due to the problems thalassaemia patients experience in tolerating regular self-administered infusions (Modell et al. 2000). Standard treatment now includes the possibility of using a licensed oral iron chelator, deferiprone (Ferriprox®, ApoPharma) or deferasirox (Exjade®, Novartis). These can help greatly where adherence to parenteral desferrioxamine infusions has been a problem, and have some additional therapeutic advantages which are described in chapter 10: monitoring and management of iron load. At least in part due to more tolerable and effective regimens using oral iron chelators, there is growing evidence that life expectancy across whole population has improved over the last two decades (Telfer et al. 2006; Borgna-Pignatti et al. 2006). Constant monitoring for complications, and their timely treatment where possible, goes hand in hand with organising regular blood transfusions and managing chelation therapy throughout the patient's lifetime. As in other chronic lifelong conditions which demand a high level of medical intervention, it is not just the technical care that affects the patient's wellbeing, but also the way in which that care is delivered. Provision of patient-centred services is one of the most important factors, and clinics should take particular care to minimise disruption to education, employment and family life, allowing patients to live as fully and normally as possible. Such care can materially improve survival by enhancing adherence to difficult treatment regimens.

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Section A: Organisation of Thalassaemia Services

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3: Networks for Care and Commissioning “We desperately need more specialist doctors and nurses outside London, there are not enough experienced medical and nursing staff in other areas.” “I don’t rely on my local centre for expert thalassaemia related queries as we don’t have anyone there who is a specialist.”

Aims To optimise care for all patients, wherever they live, by giving access to complex acute care and regular specialist multi-disciplinary input, while ensuring that routine treatment is given as conveniently as possible, close to the patient's home. To provide a service emphasising prevention, early detection and management of complications, and improved quality of life. To ensure good communication between patients and families, and the various agencies involved in their welfare, including the team in the Specialist Haemoglobinopathy Centre (SHC), the Local Haemoglobinopathy Team (LHT), Primary Care and, where relevant, social services and education.

Standards  All regions must deliver care for people with thalassaemia through a clinical network incorporating local haemoglobinopathy teams (LHT) and one or more Specialist Haemoglobinopathy Centres (SHC).  Established pathways within the network should ensure that all patients have access to an SHC – for their regular management if living nearby and for a comprehensive review of their condition and care at least once a year, at an ‘annual review visit’, if they live more distantly and receive their regular care from an LHT.  Specialist clinical advice should be available from the SHC at all times, for patients who present acutely to their local centre with complications the local team may not be experienced in managing. There should be the facility for urgent transfer of a patient to the SHC for complex care.  The network should have sufficient resources (health care professionals, management and administrative staff) to function effectively, and should develop systems for information sharing, clinical governance, accountability and staff development.  A ‘key contact’ health professional will be designated for each patient.  Patients and carers should receive regular education, supervision and support in thalassaemia care, chelation therapy and other home treatments.  All health providers within the network – primary care teams, LHTs and SHC – should record and exchange information relating to clinical events, monitoring investigations, and changes in treatment. Correspondence should always be copied to patients/carers.

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 Consent should be sought from all patients for entry of their details on the National Haemoglobinopathy Registry, and data entered in a timely fashion to assist audit and assessment of good quality outcome information.  Patients and carers should be involved in making decisions about management and delivery of care.  Patients and carers should have access to peer support groups.

Background Hospital care is, for the majority of patients with thalassaemia, inevitable – for transfusions, for often complex clinical and diagnostic assessments and their interpretation, and for decisions about chelation and other necessary medications. Ensuring that routine hospital care can be accessed locally, at times to suit the patient and family, while meeting the need for every patient to have access to skilled specialist healthcare professionals with particular interest, experience and knowledge of the condition, has led to the development of care networks. The hospital services within the networks consist of Local Haemoglobinopathy Teams, LHTs, where much routine care should be delivered, linked to a large Specialised Haemoglobinopathy Centre, SHC, where a multi-professional specialist team is based, overseeing services and individual patient management at all the linked LHTs. This is because best practice guidance changes continually, particularly about iron chelation regimens and the management of specific complications, as clinical trials and studies mature and results are disseminated and discussed. All patients should benefit from the chance to discuss their care with professionals who are highly experienced and keep themselves comprehensively informed about the condition and its management. The intention is that every patient should be known to, and seen at least once a year by, the SHC team, at an ‘annual review’ visit to ensure their management is in every aspect updated and appropriate. The content of the annual review, and arrangements for its delivery, are the subject of the next chapter. SHCs are required to agree with their LHTs an additional list of issues for which consultation in between annual reviews is required. Additionally, every patient should have access to specialist advice at any time – day or night they present with acute clinical problems, which may not be within the range of experience of their local clinicians. Hospital services for children and adults with thalassaemia, sickle cell, and other inherited anaemias, have been commissioned by NHS England as specialist services since April 2014 (Specialised Services National Definition set no 38). Commissioning is a process by which health needs are identified and services bought to meet those needs. Where possible, an evidencebased approach is used in procuring services and in monitoring their delivery. Specialist services are designated as those which are low volume and high cost or are very complex to deliver. Clinical Reference Groups (CRGs) bring together groups of clinicians, commissioners, public health experts, patients and carers to advise NHS England on the best ways that specialised services should be provided (www.england.nhs.uk/commissioning/spec-services/npc-crg/), and there is a CRG specifically for haemoglobin disorders services. CRGs lead on the development of clinical commissioning policies, service specifications and quality dashboards. They also provide advice on innovation, conduct horizon scanning, advise on service reviews, identify areas of unexplained clinical variation and guide work to reduce variation and deliver value. CRGs, through their Patient and Public Voice (PPV) members, also help ensure that any changes to the commissioning of specialised services are co-produced with patients and the public. The service specification B-08 (NHS England 2013) describes the aims and objectives of the service and pathways of care. Care will be delivered by a specialist haemoglobinopathy centre (SHC) acting in a hub and spoke model with other linked providers. The SHC, working with linked providers, is expected to deliver a network of care for all patients in the geographical region. The aim is to reduce levels of morbidity and mortality and improve the experience of all haemoglobinopathy patients by reducing inequities and improving timely access to high quality expert care.

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In summary, in relation to thalassaemia in particular, the specifications include: • Clinical leadership. • Managing the results of newborn screening and ensuring timely entry into care. • Management of complex patients using a multidisciplinary team approach. • Initiation, modification and cessation of long-term transfusion regimes. • Initiation, modification and cessation of iron chelation. • Monitoring of complications including access to cardiac and liver MR scanning to quantify tissue iron. • Acute management of severe and life threatening complications including: • Heart failure and cardiac arrhythmias. • Infection prevention and control. • Post-splenectomy sepsis. • Acute endocrine disturbances • Acute hepatic decompensation. • Long-term specific therapy for complications (complex long-term conditions management) including: • Endocrine dysfunction. • Cardiac dysfunction. • Chronic liver disease. • Bone and joint problems including osteoporosis. • Gallstones. • Ankle ulceration. • Iron overload. • Pulmonary hypertension. • Thrombosis. • Chronic pain. • Peri-operative management of thalassaemia patients requiring surgery. • Management of pregnant women with thalassaemia. • Timely access to critical care (not always at the SHC for paediatrics, but pathway to another). • Access to Bone Marrow and Stem Cell Transplantation (pathway to a recognised centre) • Clinical Governance and Audit including • Reporting all adverse events to commissioners and the National Haemoglobinopathy Registry (NHR) • Undertaking an agreed number of clinical/quality audits. • Participating in any peer review process. • Reviewing all clinical guidelines and protocols across the network including those produced by community providers. • Reviewing and amending pathways to promote integrated care. • Ensuring the quality of care provision and delivery. • Supporting local and national benchmarking. • Overseeing compliance with care pathways and standards for all patients in the network. • Providing expert care and advice at all times. • Patient and carer engagement. • Data collection, management and submission. • Clinical education and training across the network. • Leading on research and development.

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Quality Standards for the delivery of care are outlined in the service specification and have been developed by the UK Forum on Haemoglobin Disorders in conjunction with the West Midlands Quality Review Service for assessment by the peer review programme (WMQRS 2016). There is no recommended size, in terms of the numbers of patients managed, for a Specialist Centre. The demographics of people living with thalassaemia are such that very large centres exist only in the North West England, West Midlands and North and East London. Centres outside these areas who manage relatively small patient numbers are encouraged to liaise with the larger Centre teams for staff training rotations, and for discussion of complex or atypical case presentations. The idea of a national ‘MDT’ for discussion of such individual patients is being considered through the Clinical Reference Group, in conjunction with the UK Forum for Haemoglobin Disorders. It is recognised that to provide all of the Service Specifications across a whole clinical network places a great deal of responsibility on the members of the Specialist Team, and requires much additional work. How this can best be supported by the commissioning process is under current review. Recommendations for appropriate staffing are given in a workforce review (Ryan 2015). Although a degree of hospital dependence is inevitable, much routine care such as the administration of iron chelation and other medication is undertaken by the patient and family at home. People who understand fully their condition, are involved in every care decision, and are guided and supported in self-care by primary and community care staff as well as hospital teams, become truly expert patients and this helps in ensuring optimal adherence to treatment, and maximising quality of life and longevity. Focus on education and support for the family from the time of diagnosis, and throughout life, is critical. A designated ‘key contact’ health care professional, with whom the family will become familiar and comfortable, is essential for streamlining access to services, clinic appointments, transmitting results of investigations and troubleshooting medical and psychosocial complications as they occur. Regular transfusions each month are the mainstay of treatment for those with thalassaemia major, but if the organisation for delivery is poor and inflexible, this causes great inconvenience to the patient and family, and impairs quality of life. A well planned process is required, delivering treatment close to the patient's home or work. Many patients prefer to arrange their transfusions during the evening or overnight, in order not to interfere with school/college/work commitments. Revised guidance by ‘SHOT’ (serious hazards of transfusions) that ‘transfusions should be given with the same attention paid to observations whatever the time of day or night’, over-riding their previous guidance that transfusions should only be given out of hours where clinically urgent, should help units to work toward this provision (Bolton-Maggs 2014). Communication is a key element in efficient functioning of a care network. When a patient is being treated by multiple agencies, relevant information needs to be meticulously shared to avoid omission or duplication and to optimise treatment. This is more challenging but perhaps particularly important where there are communication or language difficulties. Patient-held records can be an effective way of transmitting information between clinical staff in different clinics, and patients and families, although in practice they have never become very popular or routinely used in the UK. Collecting systematic records of all affected individuals is essential in planning, commissioning, delivering and monitoring care for long term conditions. The National Haemoglobinopathy Registry (NHR – www.nhr.nhs.uk) is an established platform for collection of all necessary data. It is being continually updated and refined to maximise its use for delivery and audit of services. Every patient with thalassaemia should be given information about the NHR, and asked for consent for their details – including any adverse events and results from annual reviews – to be entered on it. Once consented, timely data entry will support many of the governance and audit requirements of the network.

Requirements  Once the diagnosis of thalassaemia is established, the parents must be given the diagnosis by a knowledgeable professional, often a specialist nurse, who can start to explain the condition 2016

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and offer some written information, and provide contact details of the UK Thalassaemia Society and any local support groups.  This should be followed up by an early clinic appointment, usually with a Paediatrician, Paediatric Haematologist, or Haematology Consultant with experience of looking after children with the condition. This may be at the LHT but, if local experience is limited, should be at the SHC. Further discussion of the condition will include the subtleties of whether regular transfusions are likely to be necessary, when they might start, and the implications of this. The importance of the family as central care-givers should be emphasised.  If the initial clinic visit is not at the SHC, a referral to the SHC should be made with a view to the family seeing the specialist team early, and before transfusion has been necessary if at all possible.  It is important to check that the information given is understood by the family, and when needed, to use health advocates who can communicate in the appropriate language and cultural context.  The family should be given the details of their ‘key contact’ at the LHT and SHC, and meet them as soon as possible.  The patient's primary care team should be offered information about the condition and advised about possible acute presentations and their significance.  Once regular care is established, arrangements are made for regular review by the SHC team at least once a year, and between times as necessary.  Clinic letters and investigation results must, throughout the care pathway, be exchanged between the LHT, SHC, and primary care team, with the patient/family copied into all correspondence.  LHTs will offer pre-transfusion compatibility testing, and organise and deliver routine transfusions once the need for them is established by the SHC. The LHT will provide regular prescriptions for medications as agreed with the SHC, check the child/adult before each transfusion in the clinic or day care setting, organise some if not all of the routine assessment checks, ‘troubleshoot’ any symptoms or problems, and offer support to the patient and family.  For patients living close to the SHC, routine and specialist care will be delivered there.  Out of hours/weekend phlebotomy, clinic appointments, and transfusion facilities should be available especially for older children and adults in full time education, and adults in employment.  The SHC will draw up and communicate with the LHTs a list of indications for which they should be contacted, in or out of hours, for advice about a patient’s condition, acute presentation or any other concern and/or for possible transfer of a patient to the Centre for complex care. The list will not be exhaustive, and the local teams are free to contact the specialist team at any time they have queries or concerns.  At the SHCs, robust arrangements must be in place to provide expert consultant advice at all times. Hospitals with single-handed consultants should consider new appointments, and all should consider the need to make formal arrangements with other centres to cover out of hours periods when the haemoglobinopathy consultant is not on call, and for times they are on leave or other absence.  Adequate numbers of sufficiently trained staff must be available at each point of care across the pathway  Transition arrangements for passage from paediatric to adult services need to be considered at both the LHT for regular care, and the SHC for specialist reviews.

Recommendations These figures assume a mixed patient group, including those with thalassaemia and sickle cell disorders, with a preponderance of the latter. In centres where there are larger numbers of thalassaemia patients, additional time is likely to be needed in the job plan.

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Medical Staffing Staff

LHT

Designated Consultant Paediatrician and/or Haematologist (depending on age spread of patients) providing a lead for the service. Thalassaemia will be a major interest and responsibility. The number of consultants will depend on the size of the Centre.

SHC ✓

Designated Paediatrician and/or Haematologist (depending on age of patients)

✓

Named deputy for each

✓

✓

Middle grade cover (SpR/ST3 or above/Staff Grade) and consultant cover available out of hours

✓

✓

As a guide, suitable PA allocation for lead consultants would be: • 1.5 PA for every 50 patients for direct clinical duties* made up as: •

Clinics including specialist annual review (2.0 hours/week)

•

Ward rounds (1.5 hours/week)

•

Day unit attendance and ad hoc consultations, on call (1.0 hour/week)

•

Clinical administration and MDT meetings (1.5 hours/week)

• 0.25 PA for every 50 patients for supporting activities: NHR and data collection, audit, teaching, patient liaison, network participation • 0.25PA CPD per consultant

Nursing Staffing The key contribution of hospital and community based nurses to the acute and chronic disease management of sickle cell and thalassaemia patients should be acknowledged and numbers should be brought into line with those of other long term condition. Job planning for specialist nurses must include adequate time to deliver RCN training competencies for hospital staff and to undertake audit and service development. Staff to cover these roles are necessary: Staff

LHT

Lead nurse for thalassaemia service, training, liaison, audit. Regular nurse(s) in ward area who can cannulate and start/supervise transfusions on day care unit, and also during evenings, overnight and weekends

SHC ✓

✓

Specialist nurse outreaching into community (responsible for home visits, teaching parents to set up desferrioxamine pump etc.)

✓ ✓

Key contact - could be any of above, or an experienced transfusion practitioner.

✓

✓

Identified deputy for key contact.

✓

✓

LHT

SHC

Psychology Staffing Staff Clinical psychology, for children and adults. Access to named psychologists.

✓ ✓

✓

LHT

SHC

Other Specialist Staffing (not necessarily all on site) Staff Consultant Cardiologist.

✓

Consultant Paediatric and Adult Endocrinologist.

✓

Consultant Hepatologist

✓

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Staff

LHT

SHC

Consultant Nephrologist

✓

Consultant Urologist

✓

Consultant Orthopaedic Surgeon

✓

Consultant General Surgeon

✓

Pulmonary Hypertension Team

✓

Fertility, contraception and sexual health services, including pre-implantation genetic diagnosis

✓

Consultant Obstetrician

✓

Dental team

✓

Allogeneic Bone Marrow Transplant team

✓

Access to other staffing and facilities Staff

LHT

SHC

Appropriate laboratory support (transfusion and other, and access to molecular diagnostics).

✓

✓

Access to full range of diagnostic imaging including MR T2* and R2 (not necessarily on site).

✓

✓

Access to translation services

✓

✓

Access to Social Worker

✓

✓

Access to Dietician

✓

✓

Administrative support sufficient to ensure proper communication between patient and family/LHT/SHC/primary care teams.

✓

✓

Personnel to handle patient data and input to National Haemoglobinopathy Registry.

✓

Facilities • Facilities for transfusion should be in a relaxed, preferable dedicated, day care area rather than in a conventional ward setting. • For children, all facilities must be separate from adult services, and should be age appropriate, with availability of play therapy for younger children and entertainment/schoolroom facilities for older children.

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4: Annual Review at Specialist Haemoglobinopathy Centre “My consultant and specialist nurse both helped me create a suitable treatment plan for the coming year. I am pleased with the service I receive.” “The medical and nursing staff need to understand how thalassaemia impacts on our lives day to day and make sure we are referred regularly for all the necessary tests.”

Aim To ensure that all children and adults will have a comprehensive assessment by specialist healthcare professionals at least yearly, or more often if necessary, to optimise their care. To ensure that patients and families are fully informed about their condition, are kept up to date about any possible treatment changes, and have a clear management plan for the year ahead.

Standards  Every person with thalassaemia will have the opportunity for their care and condition to be reviewed at least annually with a team of health care professionals who have particular experience in caring for thalassaemia disorders. This can take place during a visit to the Specialist Centre, or at an outreach clinic where members of the Specialist Team visit the local centre at which the person receives their routine care.  The assessment should cover all aspects of care including educational and lifestyle factors that may affect health or influence adherence to treatment.  Discussion of treatment options should include any new information which has become available, and an individual treatment plan for the next 12 months will be agreed.  A copy of the annual review consultation including the care plan will be copied to the patient or, for children, their parents as well as health professionals involved in their care.  Data should be entered into the annual review screens of the NHR for consented patients.  People in families affected by thalassaemia should be able to meet and gain support from other affected families at the Centre or in the community.

Background Patients with these complex multi-system disorders require input from a range of specialist health professionals and access to investigations which may not be available everywhere. An individual case review by SHC professionals at least once a year will offer all patients access to optimal specialist care regardless of where they live. The annual review is intended to be a 2016

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comprehensive assessment of every aspect of the patient's treatment and condition to assess progress and identify any areas where treatment could be improved. The National Haemoglobinopathy Registry (NHR) is a database for patients with thalassaemia and other inherited haemoglobin disorders and captures data including numbers of patients, adverse events, treatments and complications arising from transfusion, medication or iron overload. The annual review screens allow for collection of a consistent dataset. This national resource will provide information to help in future planning of service delivery and performance in relation to key outcomes of care. Participation is voluntary and all patients and their families should be given verbal and written information to enable them to give properly informed consent. The NHS standard commissioning contract for specialised services for haemoglobinopathy care for all ages (B08/S/a) stipulates that a Specialist Haemoglobinopathy Centre (SHC) • will provide (or delegate) a multidisciplinary annual review for all patients living in its geographical area either on-site or as an outreach service. This annual review will include review of cardiac and liver MRI results for patients with thalassaemia. • will register all consented patients in their geographical region on the NHR. For patients identified by the screening programme this will be at first paediatric review. The SHC are to ensure that individual records are complete and kept up to date, including adverse events and annual review data.

Requirements  The patient and family will usually visit the Centre for a pre-booked appointment. In some areas, a local agreement may be made for a Paediatrician and/or Haematologist from the SHC, often with a specialist nurse, to hold an outreach clinic. In areas where the designated SHC does not have specific thalassaemia expertise, arrangements will be made to link with another SHC with the appropriate experience.  The SHC should agree with the patient’s local team which investigations can be performed there and the results of these, together with information on clinical progress and treatment should be available at the time of annual review.  At the visit, the consultation will be with the designated Paediatrician or Haematologist. Access to other specialist team members such as specialist nurses or clinical psychologist should be provided, ideally at the same visit, or at a separate consultation, if not possible.  Assessment will be made of progress in general and a review made of the patient's and family's knowledge of the condition and they should have the opportunity to ask questions.  The review should include: – Assessment of any new or ongoing symptoms. – Adverse events over the preceding 12 months – Transfusion management; assessment of pre transfusion haemoglobin levels, any transfusion related complications. – Results of monitoring tests for iron status. – Current iron chelation regimen, adherence, and consideration of whether it can be improved in terms of tolerability and efficacy. – Review of other medication. – Prophylaxis against infection for splenectomised patients (vaccinations and a supply of antibiotics). – Attendance at the appropriate specialist clinics (cardiac, endocrine, hepatology) for his/her age and clinical status. If not referral should be made. – Weight, sitting and standing height and review of growth charts (children). – Clinical examination with particular reference to heart, liver, spleen, pubertal status in relevant age group. – Education and work activities and aspirations, and lifestyle factors which may affect health.

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– The issue of possible bone marrow transplantation, and consideration of referral to a transplant centre (see chapter 11: Referral for Blood and Marrow Transplantation ). Once a discussion has taken place this should be noted and it is not necessary to repeat at each visit, unless the family wish to revisit the question or new circumstances have arisen e.g. pregnancy, birth of another sibling. – Discussion regarding fertility and plans for conception/pregnancy, where relevant, including partner testing for any haemoglobin disorder. – A measure of emotional and psychosocial wellbeing, and discussion of the possible value of referral for psychological assessment and support.  After the visit the clinician should write a summary including any problems highlighted and recommended changes to management. Copies should be sent to the referring hospital, the GP and the patient/family.  Where test results become abnormal between annual reviews, the local team should discuss them with the SHC team to decide on the need to refer/start additional treatment.

Recommendations • Any specialist investigations should be planned so as to require the minimum possible number of hospital visits and, where logistically possible, should be combined with the annual review visit. • It should be ensured that the patient/family has access to relevant written informational material. They should know how to access the UK Thalassaemia Society and be put in touch with any local support group or organisation. Ideally they should be able to meet other patients/families at the Centre. • The annual review visit is also an opportunity to discuss with parents of an affected child plans for further pregnancies with reference to their choice regarding pre-natal diagnosis, preimplantation genetic diagnosis, and testing/storage of cord blood. • The patient's hand-held record, if used, can be completed at the end of the annual review visit. • Following the visit data should be submitted to the NHR provided consent has been given.

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5: Quality Assessments “My life would be so much easier if only the day unit was open at weekends.” “We need more specialist nurses and doctors – I cannot fault them for dedication but they are very overworked and don’t have enough time for all our problems.”

Aims To ensure that all patients with thalassaemia have access to appropriate clinical care, so as to optimise their chance of living a healthy, good-quality and long life with as few inconveniences and complications as their condition allows. To provide an external independent review of thalassaemia services in the UK with the aim of highlighting any areas of sub-optimal care and improving quality and equity of care for patients. To ensure findings from external review are presented to appropriate local and national bodies and are used to influence commissioning and policy development.

Standards  An independent external peer review of thalassaemia services should be completed every twothree years.  Results from this should be made available to the inspected services, to NHS Commissioners and NHS England.  Commissioners should designate clinical networks, support the establishment and ongoing running of the networks and review outcome data from the network at least annually.  Specialist haemoglobinopathy centres should have fail-safe mechanisms for enrolling all newborns with thalassaemia into clinical care.  Specialist and local haemoglobinopathy centres should have enough medical and nursing time to care for patients with thalassaemia, and experienced support staff, aware of the issues facing patients with thalassaemias.  There should be a clear process for transition from paediatric to adult care.  There should be access to appropriate out of hours services.  Adequate information should be provided for patients, and readily available comprehensive clinical guidelines for staff.

Background Following the development of the Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK, and similar standards for the management of patients with Sickle Cell Disease, the haemoglobinopathy community expressed a need to review services in the UK against these standards. The UK Forum on Haemoglobin Disorders, the UK Thalassaemia Society, the Sickle Cell Society, and the NHS Sickle Cell and Thalassaemia Screening Programme agreed that a peer review programme should be set up and worked with the West Midlands Quality Review Service (WMQRS) to develop this. The first programme of reviews of services for Children and Young People with Haemoglobin Disorders ran between 2010 – 11, reviewing 19 centres, and was followed by a review of Adult Services between 2012 – 13 which reviewed 32 teams. An

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overview of both of these programmes of Peer Review and the report from each participating centre are available (www.wmqrs.nhs.uk/publications) This has been succeeded by a programme of joint reviews of children and adult services which commenced in 2014 and is nearing completion at the time of writing. The first rounds of these peer reviews was intended to be developmental, aiming to improve the quality of services for children and adults with Haemoglobinopathies. Quality Standards were developed for the first peer review programme after extensive review by members of the UK Forum and patient groups and were modified for subsequent reviews. These were divided into standards looking at the following areas: • Information and Support for Patients and their Families • Staffing • Support Services • Facilities and Equipment • Organisation of Services • Guidelines and Protocols • Service Organisation and Liaison with other Services • Governance Network and Commissioning Standards are also included in the latest review programme. Peer reviewer training was provided for health professionals and patient representatives who were to be part of a review team, before each programme began. All specialist centres and nonspecialist centres with a large population of haemoglobinopathy patients were offered the opportunity to take part in the programme and although participation in the programmes has been voluntary, all invited centres agreed to be visited. Prior to the visit centres are asked to complete a self assessment against the quality standards and also to provide some background information on their service. The visit team comprises multidisciplinary health professionals (doctors, nurses, psychologists), managers, commissioners and patient and carer representatives. During the visit they review the evidence provided by the centre to demonstrate compliance with the standards, tour the facilities, interview staff and patients and assess the service against the quality standards, before producing a visit report. The programme is overseen by a steering group consisting of multidisciplinary health professionals, members of the WMQRS and patient representatives who meet regularly and review all reports. While some findings of the peer review were local issues, several themes became apparent during the course of the review programmes. These included: • The peer review programme supported national recommendations that haemoglobinopathy services should be provided by specialist haemoglobinopathy centres (SHCs) supported by local hospital centres (LHTs) providing care close to the patient’s home, but found that there were few fully functional clinical networks and those that existed were informal and often based on historical referral patterns. LHTs were identified which did not have a robust link with a SHC and where referral patterns were poorly defined or non-existent. • Data collection was poor and/or incomplete. Few of the centres reviewed during the initial visits were entering data systematically on the National Haemoglobinopathy Registry (NHR). In later visits many centres were enrolling patients on the NHR but few were routinely entering data for annual reviews or reporting all adverse events. The NHR is a valuable tool for data collection and once data is routinely entered will allow rapid and accurate collection of audit data. • Some areas did not have ‘fail-safe’ arrangements to ensure that children identified by the screening programme accessed appropriate care and SHCs could not accurately enumerate all children for whom they had responsibility in the network. This led to a lack of audit of compliance with key standards for clinical care. Most SHCs had no formal data collection support and this role was performed by medical or nursing personnel. • In almost every centre, services were provided by key medical and nursing personnel who were providing high quality care. The number of consultant and specialist nursing sessions was 2016

35


rarely adequate to manage the number of patients cared for by the service and workload of specialist staff was often unreasonably high. Staff absence was not covered robustly leading to problems in providing consistent high quality care. Poor staffing levels resulted in a lack of training and often poor quality care outside of the haemoglobinopathy team. There was inadequate planning for staff support in areas with rapidly increasing patient numbers or where staff retirement was imminent. • Provision of transition services was patchy with some services providing high quality support throughout transition and others having no transition programme. • Support services are very important in providing high quality care, for example psychology support is key to achieving good adherence to therapy for adults and children with thalassaemia. Access to support services such as psychology and social work was variable and often not readily available. • Most services could not provide planned care (transfusions, blood tests, clinics visits) outside normal working/school hours and this led to patients missing 1.5 to 2 days of education or work per month. • The Quality Standards listed a range of patient information which should be available including description of services and information about thalassaemia and its treatment and complications. Whilst good quality information was available in some centres, in others it was limited or of poor quality. • Engagement with service users and responsiveness to user feedback was variable between different services. This has been encouraged in the most recent round of peer reviews by provision of a patient survey which sites are expected to complete prior to their visit. • A number of clinical guidelines were listed in the Quality Standards but were not available in all centres visited. These included: • Checklists for first out-patient appointment, routine monitoring and annual review • Transfusion guidelines including indications for transfusion, investigations prior to first transfusion and recommended number of cannulation attempts • Chelation therapy, including monitoring of iron overload • Management of acute and chronic complications of thalassaemia • Indications for referral for bone marrow transplantation • Management of non-transfusion-dependent thalassaemia

Requirements  Each SHC should have clinical responsibility for a defined geographical area which has been agreed with the specialist commissioners. This clinical network should include SHCs designated for care of children and adults with thalassaemia, LHTs/linked providers and Community Care Providers  Each SHC should monitor annual patient data from their network which should include as a minimum – Number of thalassaemia patients under active care – Number of new thalassaemia patients (newly diagnosed patients and transfers) – Number of thalassaemia patients having annual reviews performed – Numbers of thalassaemia patients on long term transfusion and on iron chelation – Adverse events in thalassaemia patients – Numbers of thalassaemia patients who died or became lost to follow up in the last year – This should be accompanied by patient enrolment onto the NHR and systematic reporting of annual reviews and adverse events.  It is acknowledged that not all babies with thalassaemia will be identified by the newborn screening programme, but SHCs should have robust ‘fail-safe’ mechanisms for identified newborns and any other infants as they are diagnosed, into appropriate clinical care.

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 Each SHC and LHT should have appropriate consultant, other medical, and nursing time for the number of thalassaemia patients under their care. This should include adequate cover for staff absence.  Each SHC and LHT should have a clear transition process. This should include a named coordinator for transfer of care, guidelines for transition (with age of transition), joint meeting between children’s and adult services, patient information about transition and arrangements for monitoring immediately following transition  SHCs should have access to appropriate levels of support services (eg psychologists, social workers, play therapists) with an awareness of issues facing patients with thalassaemia  SHCs and LHTs should provide facilities for out of hours transfusions, phlebotomy and outpatient clinics appropriate to the local population.  SHCs and LHTs should have a full range of clinical guidelines to aid in clinical management of patients with thalassaemia. The LHTs should have access to all the guidelines developed by the SHCs, and can adapt these for local use if necessary. Alterations should be agreed by the SHC.  Commissioners should agree the configuration of clinical networks and ensure that the SHCs have sufficient resource to support the network.  Commissioners should ensure that all LHTs have formal links and referral pathways to SHCs so that all thalassaemia patients can be offered annual review, and management guidance as and when needed, by appropriate specialist clinicians.

Recommendations • Commissioners should monitor the quality of care provided by SHCs and LHTs by reviewing their annual data outputs • ‘Fail-safe’ mechanisms to enrol any newborns into care should be reviewed at least annually with the newborn screening laboratory. • SHCs should have adequate resource to allow appropriate data collection which should include consent and entry, annual review and adverse reporting on the NHR. • All Trusts should ensure that all patients with thalassaemia have appropriate access to support services including psychology, social work and play therapy • SHCs and LHTs should have a full range of information available for patients and carers and should have mechanisms for receiving feedback from patients and responding to this feedback. An annual patient survey would be one way of meeting this. • NHS England should ensure there is support for an on-going peer review programme.

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Section B: Core Management Standards

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6: Psychosocial Issues in Thalassaemia “People don't and can't understand thalassaemia as they can’t see from the outside how unwell you are and what you're going through every day of your life – especially when your haemoglobin is dropping before transfusion. It’s like looking at a house, it might look OK on the outside but you can’t tell what's happening on the inside.” “I wish they would offer counselling services to people who have thalassemia.” “Some people think you are diseased and don't have a right to the same emotions and relationships as everyone else. You are broken.” “I find it difficult to form relationships. The fear of negative attitudes from people plus my own lack of self-esteem and body image issues mean I am shy when meeting new people.”

Aims To promote the patient’s capacity to adapt optimally to having thalassaemia. To improve quality of life and emotional wellbeing among patients. To support patients to manage their health alongside their normal lives. To minimise the negative impact of thalassaemia on emotional wellbeing. To reduce levels of emotional distress and the effect such distress can have on physical wellbeing and engagement with treatment.

Standards  Consideration of the psychosocial demands and support needs of living with thalassaemia is a key role and responsibility for all professionals involved in the provision of care for people with this condition.  Consideration of the family context and developmental/life stage of the person with thalassaemia is key to ensuring that care and treatment recommendations are individually tailored and appropriate for each patient.  Psychosocial support alongside specialist psychological care should be provided as a standard part of thalassaemia clinical care, in both paediatric and adult services.  Core staffing of Specialist Haemoglobinopathy Centres should include a clinical psychologist with a special interest and experience in thalassaemia.

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Background Living with physical illness can be difficult and upsetting (Christie and Khatum 2012). The physical and emotional disruption caused by illness, along with the potential demands and the toll ill health places on the individual can be substantial. Illness challenges our sense of health, control, stability and self, and impacts our day to day life and relationships with others. Chronic illness can have particularly life-changing effects: rather than involving a full return to health and normal life, it demands that the individual must adjust to and accept some level of ill health and manage periods of remission and exacerbation over time (Rolland 1984; Rolland 1987). Serious chronic illness requires permanent changes to normal life and an ability on the part of the individual to continually readjust and redefine goals and personal identity, making changes to his/her way of living and being (Fennell 2003). As a chronic, lifelong and life-limiting condition, thalassaemia poses multiple and severe challenges (Anionwu and Atkin 2001; Politis 1998). Alongside the physical symptoms of thalassaemia, and its impact on family, relationships, emotional wellbeing and quality of life, the child or adult with thalassaemia must also cope with invasive, complex and demanding treatments, frequent hospital visits, and a lifelong reliance on health services. Thalassaemia has an impact on both physical and emotional functioning as the individual must adjust to the impact illness has on his/her physical wellbeing and on his/her hopes and ambitions for life. Feelings of difference, uncertainty, anxiety, helplessness and loss are common and the individual must make physical and emotional adaptations to build a life that incorporates illness, managing physical symptoms and treatments while struggling to maintain a sense of self-worth and normalcy (Atkin and Ahmad 2001; Georganda 1998). Not only does growing up with a chronic medical condition present significant challenges to children in accomplishing developmental tasks (Eiser 1993; Immelt 2006) but high rates of depression and anxiety are consistently found among seriously physically ill adult populations (Royal College of Psychiatrists, 2012). Given that a number of psychosocial factors are known to influence patient adjustment and adherence (Goldbeck et al. 2000; Joshi 1998), failing to provide psychosocial care, as part of standard care, in thalassaemia runs the risk that higher levels of untreated emotional distress will lead to lower treatment adherence, poorer self-management and reduced clinical outcomes. Many patients acknowledge that the ways in which their doctors and nurses approach them, and the messages and expectations they convey in clinical interactions, are centrally important to the way in which they think about themselves and their illness, so the psychosocial wellbeing of the individual needs to be a significant concern for the whole team.

Requirements  The psychosocial needs and challenges faced by thalassaemia patients at different stages of life should be prioritised, to provide comprehensive and effective care. Psychological support should be available to address a variety of challenges associated with thalassaemia including, but not limited to, adjustment difficulties, poor self-esteem, low mood, health anxieties, needle phobia, treatment compliance, school and work difficulties, relationship problems and cultural issues.  Comprehensive care requires a multidisciplinary biopsychosocial team approach and regular multidisciplinary meetings.  A clinical psychologist should be an embedded member of the multidisciplinary team.  All specialist staff should be aware of the importance of psychosocial issues in providing care for people with thalassaemia and should have access to training, support, consultation or supervision from a psychologist with a special interest in thalassaemia.  Patients should have access to specialist psychology services; they should have the opportunity to self-refer and, where there are people from within the same family using the service, patients should be able to seek support from another clinician if requested. The opportunity for individual, couple and family sessions should be available.

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 Where psychological difficulties are suspected, a referral to a clinical psychologist should first be discussed and agreed with the patient.  Psychology assessments and reviews should include an overview of psychological and social aspects of the individual including details of their development, life stage, mental health history, family, relationships, schooling, employment, understanding of thalassaemia, coping skills, health beliefs and issues of self-esteem and identity.  Diagnosis of a child with thalassaemia is a challenging time for families and appropriate support should be available to enable the family to discuss the diagnosis, management and overall psychosocial impact on the child and family.  Paediatric services should utilise a developmental framework and have regular multidisciplinary reviews of all children within the service. Reviews should take place at key developmental milestones and after important medical, life or family events.  If cognitive or developmental problems are suspected, a referral should be made to clinical psychology for an initial assessment and a further referral made, if necessary, on to a specialist neuropsychologist.  Transition from paediatric to the adult care is stressful for young adults and their families, and it is important to provide psychosocial support to ensure that optimal care continues throughout adult life. Paediatric and adult centres should collaborate to ease transition using a standardised process to ensure that the proper steps are taken to equip and prepare the young person. Transition should not take place during a time of acute illness or another period of stress.  Where serious mental health difficulties or psychiatric problems are identified, referral to a secondary child or adult mental health service should be considered and, if possible, discussed with the team psychologist in a timely fashion.  If issues of safeguarding or child protection arise in regard to the safety of a child or an adult during the course of clinical care (whether the person at risk is the patient of the service or not), staff should promptly seek guidance by referring to their local safeguarding and child protection policies and guidelines, and by discussing directly with their organisation’s Safeguarding Lead.  All specialist staff should be aware of the importance of cultural influences on health and have access to training in cross-cultural work. Access to professional interpreters should be available and staff should be experienced in working with interpreters.  Information should be made available in a variety of formats, including verbal and written. Information given verbally should be adequately documented and written information should be provided in the patient’s preferred language. Information should be age appropriate and given at repeated points during the course of the condition and at times when changes in treatment or in the course of the condition occur.

Recommendations • Best practice should include a multidisciplinary assessment of all new patients and regular psychosocial review and discussion of all patients. • Specialist psychological support should be made available at critical milestones in patients’ lives including initial diagnosis, first transfusion, start of chelation, puberty, transition to adult care, and other major life events such as university, first employment, marriage, pregnancy, and parenthood. • The opportunity for patients to meet one another at specialist facilitated support groups within the service should be provided as a standard part of care and on an ongoing basis. • To promote adherence, recommended treatments should take into account the patient’s developmental level, family structure, cultural ideas around illness and treatment, social context and life demands. The constraints imposed by treatment should also be considered and wherever possible some flexibility incorporated to accommodate any minor difficulties and issues. Patients should, whenever possible, be involved fully in decisions and details about treatment regimes. Changes in treatment should always be discussed fully, and the rationale 2016

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and reasons for any changes made clear. Information about treatment options, including the relative benefits or disadvantages and the potential consequences of non-adherence to should be made available to patients. Patients should also be involved in monitoring their progress, for example ferritin levels, and the results of imaging tests quantifying tissue iron, so that their understanding of the impact of adherence and non-adherence is enhanced. More regular reviews can prove helpful in initially establishing a routine for a new treatment regime. • Planning for transition from paediatric to adult care settings should start several years in advance, educating the adolescent about the biological, medical, and psychosocial aspects of thalassaemia, and equipping him/her with the skills to become responsible and independent in caring for his/her health. To ease transition and reduce anxiety, the process works best if individualised to take into account the developmental stage and readiness of the patient and family to take on new responsibilities. Following transition, adult patients should be followed up routinely to ensure that they are receiving optimal care and appropriate psychosocial support. • Standard annual reviews of patients should include a measure of emotional wellbeing to monitor psychosocial well-being among patients in order to identify any difficulties proactively, providing prompt psychological assessment and early support and treatment, if necessary. • Wherever possible when breaking bad news the patient’s support networks should be included. Staff should remain aware of the significant impact bad news can have on patients, and should be prepared for a range of emotional responses from the patient including anger, denial, shock or distress. Staff should be trained and supported in breaking bad news. They should be prepared to offer support in accepting losses associated with the bad news and in fostering realistic hope. Giving false promises should be avoided. Staff should remain alert to the possibility of depression in response to bad news, and the impact low mood can have on motivation to adhere to medical regimes. Where appropriate, support from or referral to the psychologist should be considered.

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7: Initial Management of the Newly Diagnosed Infant “Getting our daughter's diagnosis felt almost like a bereavement. It is like any loss or perceived loss, where only the passage of time and the realisation that your child can have a fairly normal life helps you get over it."

Aims To establish the correct diagnosis in an affected infant promptly, and initiate an appropriate and timely management programme. To ensure the family has a good level of understanding of the condition, and feels well supported in the early weeks after diagnosis, and to minimise distress by communicating information and advice in a way which is appropriate to their culture and language.

Standards  Diagnosis of a child with a serious thalassaemia syndrome will be timely and accurate. It should be established as soon as possible after birth, and should include globin genotype.  The neonatal heel prick test is a screening, not diagnostic, test and early confirmation is required.  The child must be monitored closely to determine the likely clinical course.  The family should be informed fully and sensitively from the outset once the diagnosis is confirmed, by appropriately experienced professionals, with the use of a culturally-appropriate health advocate if necessary, and with the opportunity for full discussion. Suitable written information should be given to them.  A management plan tailored to the individual child must be agreed and implemented.  The family will meet their ‘key contact’ within the clinical team, and given contact numbers for subsequent use.  The family should be informed about the National Haemoglobinopathy Registry and asked to give consent for the child's details to be recorded on it.  The family should be given the contact details for the UK Thalassaemia Society and any local support group.

Background Learning that their infant has a serious blood condition inevitably comes as a shock to parents. Parents should have been made aware of their risk of having an affected child through screening and counselling during pregnancy. This counselling should have included information about inheritance, the option of pre-natal diagnosis and other choices, and the effects of thalassaemia and its treatment on the child and the family. It should be backed up by suitable written information. If the risk was not identified during the pregnancy, affected infants may be identified through the newborn screening programme. This is a screening test, and not all cases of thalassaemia will be identified. If the test shows ‘haemoglobin F only’, follow up is necessary and diagnostic

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confirmatory tests should be performed. If undiagnosed in the neonatal period, the child is likely to present with failure to thrive, poor feeding and other non-specific symptoms of anaemia and may have an enlarged spleen and liver. Depending on the level of haemoglobin at this time, initial red cell transfusion may be urgently required. Whenever the diagnosis is made, the way in which it is conveyed to the parents, and the initial conversations they have with professionals, will colour their expectations and attitudes. The first discussions must therefore be accurate, unhurried, considered and sensitive. The fact that there is a ‘grey scale’ of transfusion dependency should be explained, and parents should understand that it is usually not possible to predict the severity of the condition, or the need for transfusions, from the outset. Children need to be monitored carefully for signs of poor growth, failure to thrive, complications of anaemia and bone marrow expansion – clinical features indicative of the need for regular transfusion. Genetic analysis usually, but not always, helps to predict the clinical phenotype. Routine DNA testing should therefore include β globin genotype, α globin genotype and a determinant of persistent fetal haemoglobin production (the Xmn1 C→T polymorphism) (Ho et al. 1998).

Requirements  The diagnosis should be anticipated from antenatal screening, and established by prenatal diagnosis where requested or by neonatal testing. If not, affected infants may be identified through the newborn screening programme. The baby and parents should be seen for testing as soon as possible and preferably within two weeks. If the diagnosis has not been made at these stages, and the presentation is a clinical one, then assessment and treatment may be urgent, within one to two days.  Haematological and DNA diagnosis should be established as soon as possible by the following tests: – Full blood count and blood film examination. – Haemoglobin analysis by electrophoresis or high performance liquid chromatography (HPLC), β and α globin genotyping and Xmn1 C→T polymorphism.  Family studies may be informative, and the parents should also be tested if results are not available from prior screening.  Once the diagnosis of thalassaemia is established, the parents must be given the diagnosis by a knowledgeable professional, often a specialist nurse, who can start to explain the condition and offer some written information as well as contact numbers for any urgent concerns or questions.  This should be followed up by an early clinic appointment, usually with a consultant paediatrician, paediatric haematologist, or haematologist with experience of looking after children with the condition. This may be at the local clinic, with the LHT, but if local experience is limited, should be at the most convenient specialist centre, SHC.  If the initial visit is at the local clinic, staff seeing the family should discuss details of the case with the centre beforehand, and set up an appointment for the family to be seen there soon after.  It should be emphasised that the clinical phenotype cannot be predicted accurately in the early stages, and that the child will be monitored carefully for clinical signs indicative of the need to commence transfusion, when that might be, and the implications of this.  The importance of the family as central care-givers should be emphasised.  The arrangements for care should be discussed – wholly at the Centre if they live near, or based at the local linked hospital if more convenient – and the plan for regular, at least annual, review at the Centre with additional contact whenever required should be explained.  Appropriate written information should be made available. The family should additionally be given the contact details for the UK Thalassaemia Society and any local support groups.  The parents should meet and exchange contact details with their local key contact staff member/s, and the team psychologist, and offered support.

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 After the visit a written summary, covering the discussion and follow up arrangements, should be exchanged between local clinic and specialist centre, and copies sent to the GP and the family.

Recommendations • For babies identified by the screening programme, an initial home visit may be preferred. Where the parents already have a relationship with a specialist nurse counsellor, from discussions in the antenatal period, s/he may be the best person to make this contact. The nurse can then accompany the family to the first hospital consultation soon after. • There should be no delay in referral following suspected diagnosis because the child remains clinically well: important information is given, discussions take place and investigations to confirm the diagnosis should be instigated at this stage. • Ample time should be given to enable parents to ask questions and clarify issues. A professional interpreter is essential at this consultation if the family are not primary English speakers. If only one parent is present, it is advisable that a friend or relative accompanies them to help them to remember afterwards what was discussed. Strenuous efforts should be made to involve both parents from the start. When both attend, it is important to be sure that each has a chance to ask his/her own questions and discuss his/her own issues. • The initial meeting is likely to be dominated by the family's need to understand the nature and implications of the child's newly diagnosed condition. Genetic counselling, with regard to options in future pregnancies, can be mentioned but it is better to arrange a further meeting to address this issue, although this should not be long delayed. At this meeting there should also be discussion of the implications of possible carrier status in siblings and other family members, who should be offered testing. • During the early clinic visits, treatment options for the child in future should be discussed including the different options for iron chelation and the availability of stem cell transplantation. • Families should be made aware of the need for frequent monitoring of growth, development, and blood test results. • Where possible, the family should be given the opportunity to meet with other families who have children with thalassaemia.

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8: Decision to Start Regular Transfusion "I remember the nurse coming to take her to be cannulated, my heart pounding, the tears, the screams and the little hands that wouldn't let go."

“Good clinical judgement cannot be replaced by any kind of clear instructions regarding decisions whether to transfuse a patient“ Professor Dimitris Loukopoulos, Thalassaemia International Federation Conference, Palermo, October 2003

Aims To distinguish carefully, using clinical and DNA-based assessments, between infants with transfusion-dependent thalassaemia: thalassaemia major, and those who can maintain acceptable health and development without transfusion: intermedia or non-transfusiondependent-thalassaemia (NTDT). To initiate transfusion therapy in thalassaemia major before the infant/child develops complications of anaemia and of bone marrow expansion. To avoid unnecessary transfusion in thalassaemia intermedia.

Standards  Infants with β thalassaemia will be monitored carefully for clinical signs indicative of the need for transfusion. Transfusion will be started promptly when there is clinical evidence of severe anaemia, failure to thrive and/or thalassaemic bone deformity.  Infants and children with a milder ‘thalassaemia intermedia’ phenotype will be identified clinically and not subjected to regular transfusion inappropriately.  Extended red cell phenotype and genotype should be performed before starting regular transfusions to ensure compatible blood is transfused and to reduce the risk of alloimmunisation.  Before a first transfusion, a course of hepatitis B vaccinations should be started, and completed if possible.

Background The decision about when to start red cell transfusions in a child with β thalassaemia is a subtle and important one. There will be some indication about likely clinical severity and likely transfusion dependency from the β globin genotype, but ultimately the decision is a clinical one. The difference between ‘major’ and ‘intermedia’ is not absolute or predictable. At a given untransfused haemoglobin level, some children apparently thrive, grow and have no clinical problems while others are clearly failing to thrive. A decision to treat cannot be made on haemoglobin level alone and

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needs to include consideration if the child is thriving or not, taking into account the parents’ opinions; also height velocity, weight gain and spleen size. In the past, some children have been transfused to the point of iron toxicity who would probably have been better without regular transfusion at all. The decision about starting transfusion must always be made by – or, if urgent, after discussion with – a clinician with specific experience in this area, in a Specialist Haemoglobinopathy Centre, after detailed evaluation of the child. Usually, a decision to commence transfusion should be based on the presence of anaemia (below 70 g/l on two occasions 1 – 2 weeks apart) which is accompanied by inappropriate fatigue, poor feeding, developmental delay or regression, faltering growth, or any symptoms or signs of cardiac failure. It should be ensured that there are no correctable problems such as iron deficiency or intercurrent infection, or compounding factors such as G6PD deficiency. Into the balance should be included consideration of other factors such as age at presentation or first symptoms, increasing splenomegaly, any evidence of bony expansion or changing appearance of facial bones. Sometimes there is an ‘acute’ anaemia, for example due to a viral infection, in a child who otherwise can maintain a satisfactory haemoglobin without regular transfusion. It is therefore reasonable to give a single transfusion initially, and then wait and reassess whether the indication for transfusion recurs. If the haemoglobin falls again promptly, it is reasonable to assume longer term dependency, and to plan for regular transfusions. Where possible, a decision to start regular transfusions should not be delayed until after the 3 rd year, as the risk of alloimmunisation and of developing multiple red cell antibodies increases, with subsequent difficulty in finding suitable units for transfusion. In practice, in children who are going to need regular transfusion this is normally manifest sooner than the age of 3. Where transfusion is started later because of fall in height velocity or bony changes (often intermedia) it should not be assumed that lifelong transfusion will then be necessary. After maximum height is achieved, and bones are fused, in some cases it is possible to 'wean off' and then stop regular transfusions entirely, although the patient still needs to be carefully monitored for other complications (see chapter 24: Management of Non-Transfusion-Dependent Thalassaemias).

Requirements  After diagnosis, infants will be monitored regularly in the local clinic in liaison with the specialist centre. From the age of 3 months, these visits should be at least monthly, until the clinical phenotype is established.  Monitoring will include history of any feeding concerns, infections, ill health and developmental delay. Examination will include an assessment of growth, bone expansion (including head circumference) and hepatosplenomegaly. Haemoglobin level should be checked at least monthly.  The decision to initiate regular transfusion should be made by, or in consultation with, the designated clinician in the Centre.  Before the first transfusion, the investigations in Table 8.1 should be carried out. It is assumed that DNA studies have already been undertaken previously, at diagnosis. If not, they should be sent prior to the first transfusion.

Table 8.1. Investigations prior to first transfusion Specialty

Investigations

Haematology

Serial Hb measurements; G6PD screen and assay if low

Transfusion

Full red cell extended phenotype and genotype (C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis)

Biochemistry

LFT and baseline ferritin assay

Microbiology

Hepatitis B surface antigen; Hepatitis C antibody; HIV antibody

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9: Red Cell Transfusion “Junior doctors need to listen to us when we tell them where to cannulate us and which cannula to use and not have the superior attitude that they know best. We know our own veins.” “We need flexible services to accommodate work routines. If it were not for my consultant arranging weekend transfusion for me at another hospital I would have lost my job.”

Aims To ensure that children are transfused to an appropriate level to promote growth and wellbeing. To prevent complications of under-transfusion. To ensure that transfusions are given safely and that the transfusion programme causes minimum disruption to everyday life.

Standards  Trough haemoglobin levels should be maintained ~ 90 – 105g/l.  Blood must be ABO compatible and antigen negative for any clinically significant antibodies the patient is known to have, or to have had previously identified even if not currently detectable. It should be fully matched for all the Rh antigens and K.  Units should be less than 2 weeks old and, in adults, of larger volume where possible.  There should be a clear record of patient’s transfusion requirements outlining volume, frequency and target haemoglobin.  Transfusions will be given on each occasion in a designated age-appropriate area with suitable facilities, experienced regular named nurses and familiar supervising medical team.  Cannulation will be undertaken by an experienced nurse, doctor or phlebotomist.  Pre-arranged transfusions should be started within 30 minutes of the patient’s arrival.  Good transfusion practice must be observed.

Background Blood transfusions are essential in children with thalassaemia major enabling normal growth and development. In adults regular transfusions remain necessary to maintain life, and if given appropriately will minimise the symptoms of anaemia and allow a good quality of life. A haemoglobin level maintained above 90-105 g/l is sufficient to inhibit bone marrow expansion and minimise transfusion iron loading in most patients (Cazzola et al. 1995; Cazzola et al. 1997; Pasricha 2014). Occasional patients with cardiac disease, extramedullary haematopoiesis and/or inadequate bone marrow suppression benefit from higher transfusion thresholds of 110-120g/l although there is little published evidence on this. Transfusing to above a post-transfusion level of 150 g/l risks stroke, hyperviscosity symptoms and increases the iron burden and is not recommended. Transfusions are usually given regularly every 2-4 weeks. However intervals vary from patient to patient and should be agreed between clinician and patient depending on the clinical response to anaemia/transfusions and pragmatic lifestyle decisions. In adults each unit of red blood cells is

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usually administered over 1-3 hours. The volume in red cell units varies from approximately 220 to 320 ml. In adults units of larger volume (greater than 280 ml) can minimise the number of units required and thus donor exposure. Although there is no clear evidence for this, fresher units may reduce the frequency of transfusion therefore units less than 14 days old are preferred. For calculations of blood volumes to be given to children the following calculation can be used (adapted from New et al. 2016 for the BCSH): Volume to transfuse (ml)

Desired Hb (g/l) =

−

actual Hb (g/l)

×

weight (kg)

×4

______________________________________________________________________________________

10

To reduce donor exposure, transfusions are not normally given to the nearest ml, so for example if the calculated volume is 330 ml and one matched unit is identified containing 305 ml, part of a second unit would not be necessary. Provision of red cell units for transfusion-dependent patients requires special considerations. Efforts must be taken to minimise the likelihood of antibody production, or alloimmunisation, which may delay the provision of blood and exposes the patients to the additional risk of a haemolytic transfusion reaction. Reported rates of alloimmunisation vary widely in the literature as do practices for the degree of matching red cells. For all patients with thalassaemia it is recommended that blood should be matched for all the Rh antigens (D, C, c, E, e) and Kell (K) to minimise this risk. The patient’s full red cell phenotype/genotype should be determined before the first transfusion is given. Where patients have already been transfused samples can be referred to NHS Blood and Transplant (NHSBT) for genotyping. It is sensible for these patients to have genotype/phenotype records held by NHSBT where records can be accessed by all centres via the electronic reporting system (Sp-ICE). The risks associated with regular red cell transfusion include acute and delayed transfusion reactions, alloimmunisation, transmission of microbial infections and, in the medium and longterm, iron overload. Serious reactions due to misidentification can be minimised by meticulous attention to good transfusion practice and by ensuring national guidance is followed (BCSH 2012a; BSQR 2005). Transmission of viral infections are uncommon in the UK; however, there is always a small risk of infection from units donated during the ‘window-period’ of infectivity: between the donor contracting the infection and developing the detectable antibody, or from blood-borne pathogens not currently tested for by the NHSBT. The greatest risk to patients receiving transfusion is human error within the transfusion process (SHOT Report 2014). This risk can be reduced by empowering these regularly transfused patients to understand the product that they should be receiving, and the checking processes that staff should undergo prior to and during the transfusion, and to challenge staff if they have any concerns. Patients or parents should be consented prior to starting blood transfusions to ensure they understand these risks, using the appropriate organisational policy and forms. Adverse event management and reporting is essential in maintaining good transfusion practice and identifying methods of risk reduction. Reporting errors and incidents in line with Blood Safety and Quality Regulations (BSQR 2005) to MHRA/SHOT is mandated and local incident reporting, for the purposes of learning, is highly recommended. In addition the National Haemoglobinopathy Registry encourages reporting of harm to patients with thalassaemia as a result of transfusion. For the patient and the family, the organisation and efficiency of administering transfusions can have a major effect on the quality of life. The process includes attending for a blood sample, for pre-transfusion testing, usually within 72 hours of the transfusion, although this may be extended to seven days in some uncomplicated patients (BCSH 2012a). Availability of out of hours services, for phlebotomy and for transfusion, is greatly welcomed by patients and families. An intravenous cannula must be inserted which can be difficult and traumatic, particularly if the veins are hard to find. Cannulation done inexpertly increases anxiety and distress, and can damage veins, making future access more difficult. Patients may be extremely anxious about cannulation, and it is imperative to preserve the veins since the patient is dependent on life-long venous access. Anxiety about this key step may be an indication to refer to a psychologist or play therapist to assist with on-going management. Cannulation should be performed by 2016

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experienced staff with an understanding of the condition and good trust relationship with the patient. Indwelling catheters are not regularly used because as people with thalassaemia, especially if splenectomised, are at increased risk of venous thromboembolism. If considering their use, it is recommended that expect opinion is sought from the Specialist Haemoglobinopathy Centre, SHC, and consideration given to the most appropriate from of thromboprophylaxis. The transfusion itself usually takes 4-6 hours. Each unit should be carefully checked ensuring all patients identification details match with observations and care during the transfusion being given in line with national and local guidance (NICE 2015; BCSH 2009). Where families are able to fit blood sampling and blood transfusions conveniently around their other activities and the time taken at each visit is kept to a minimum, quality of life and motivation to adhere to treatment is enhanced. Transfusion away from a hospital setting is not usual; however where home care is considered there must be policies in place to ensure safe transfusion practice.

Requirements  The patient should be reviewed prior to each transfusion by a trained and authorised health care professional. The pre-transfusion haemoglobin level must be checked, to ensure that the planned transfusion is appropriate, and there must be an opportunity for the patient/family to discuss any problems or issues.  There should be a review with the designated clinician at least every 3 months in addition to the formal Annual Review visit at the SHC.  Pre-transfusion haemoglobin level should be between 90 – 105 g/l; transfusion interval is usually between 3 and 4 weeks.  ABO compatible red cell units which are matched for Rh (D, C, c, E, e) and Kell (K) blood group antigens must be selected.  The patient’s extended red cell genotype (or phenotype) should be determined before transfusions are given.  Pre transfusion laboratory testing should be performed in line with national guidance (BCSH 2012a) and Blood Safety and Quality regulations (BSQR 2005).  UK Blood Service, SaBTO or BCSH recommendations regarding the provision of special requirements should be referred to and followed where indicated. For example washed red cells may be beneficial for patients who have repeated severe allergic reactions, and irradiated components, cytomegalovirus (CMV) negative and/or hepatitis E virus (HEV) negative may be required in thalassaemia patients who have had or are to receive stem cell transplant. (BCSH 2012b; BCSH 2010; SaBTO 2012; SaBTO 2015).  Hospitals involved with the routine care of patients with thalassaemia must have a written transfusion policy with specific reference to the transfusion and provision of blood for these patients. It should specify where the transfusions will usually be given, the procedures for checking red cell units, setting up the transfusion, maximum rate and volume of transfusion, monitoring for reactions and actions to be instituted if a reaction is suspected. Staff should be aware of the policy and should be given regular training, and adherence to the policy should be audited.  Consent for transfusion should be recorded using the organisations policy for consenting long term multi-transfused patients (SaBTO 2011)  Transfusions should be given in a familiar clinical area by regular staff who are experienced in setting up and supervising transfusions. No more than 3 attempts to site a cannula should be made by any one individual.  Options for indwelling central venous access e.g. Vascuport or Port-a-cath should be discussed with the team at the Specialist Haemoglobinopathy Centre, if cannulation is or becomes difficult, although the risks of infection and particularly thrombosis need to be considered, and formal anticoagulation may be recommended.

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 Facilities for out-of-hours provision are a key requirement, and become increasingly important for older children and adults in full time education or employment.  A nurse should be in continuous attendance throughout the transfusion, at whatever time of day or night.  Transfusion reactions should be investigated and managed according to the BCSH guideline on the investigation and management of acute transfusion reactions (BCSH 2012b)  All adverse events and near misses should be externally reported to MHRA/SHOT in line with BSQR (2005).  Laboratories providing components for transfusion should be accredited.

Recommendations • It is good practice to measure a post transfusion Hb level occasionally and to have clearly documented details of transfusions given over the past year so that annual transfusional iron loading can be calculated • Adverse events, especially if there is any element of human error, should additionally be reported through the hospital’s incident reporting policy, for investigation and learning. • There should be regular monitoring of patients to ensure transfusion intervals and volume is providing maximum health benefits while minimising the risks of iron loading and donor exposure, and is meeting their needs both physically and socially. • All staff involved in the transfusion of patients with thalassaemia (laboratory and ward) should have awareness of these standards.

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10: Monitoring and Management of Iron Load "I am very good with my chelation and as a kid I used to be on the pump very religiously 6 nights a week 1 night off. Now I'm on Exjade a true godsend." “I sometimes forget the pump, not deliberately but due to life, e.g. coping with the kids, wife, job, etc.” “I find chelation is a process that needs to have the flexibility to adjust to suit the health and circumstances of each person during different life stages.” “The treatment is inconvenient and painful. It’s difficult but I am trying very hard to have it every day.”

Aims To monitor body iron stores accurately, minimise iron accumulation, and prevent tissue damage and organ dysfunction resulting from transfusion iron overload. For patients who are already iron loaded, to reduce body iron load and minimise the toxic effects of intracellular and extracellular iron. To monitor for adverse effects of iron chelator drugs, and to adjust therapy to minimise associated morbidity.

Standards  A protocol for iron chelation therapy in children and adults should be shared between the Specialist Haemoglobinopathy Centre and Local Hospital Teams within the clinical network, and reviewed at regular intervals. This should be based on current published evidence, expert opinion, and national specialist commissioning guidance.  Decisions about initiating and changing chelation therapy should be made by the thalassaemia specialist, taking into account the preferences of the patient and carers, and the views of other involved health care workers.  Patients and carers should be informed about benefits and possible adverse effects of each option and offered information in formats appropriate for age, language and literacy, with health advocacy as needed. The decision process should be recorded in the patient's records.  Patients and carers should be supported in adhering to chelation therapy using a multidisciplinary team approach including clinic doctors, nurse specialists, clinical psychologists, and play therapists for children. Peer support should be encouraged.  Adherence should be monitored regularly, and problems carefully identified and addressed in a non-judgmental manner.  All patients should have access to Cardiac MRI for assessment of myocardial iron overload and cardiac function, and to liver MRI for assessment of liver iron concentration. The MRI methodology should be standardised and validated.

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 Patients should be carefully monitored for side effects of iron chelation therapy, and treatment interrupted or reduced promptly to avoid serious toxicity.  The outcomes of chelation therapy within local clinics and the clinical haemoglobinopathy network should be audited regularly.

Background Introduction Iron overload in thalassaemia major (TM) is usually fatal in the second or third decade of life if not treated. Toxic effects are attributed to non-transferrin bound iron (NTBI) in the plasma and toxic unbound iron in intracellular compartments. These accumulate when the normal physiological mechanisms which sequester iron are overwhelmed (Cabantchik, Breuer et al. 2005). The majority of deaths, even when effective iron chelation therapy is available, are due to iron related cardiomyopathy, presenting as cardiac arrhythmias and cardiac failure (Borgna-Pignatti, Rugolotto et al. 2004). Iron toxicity also causes hypothalamic and pituitary damage resulting in growth hormone and gonadotrophin deficiency, presenting as short stature, delayed or absent puberty, and infertility (Olivieri and Brittenham 1997). Other endocrine problems include glucose intolerance, diabetes mellitus, hypothyroidism and hypoparathyroidism (Cunningham, Macklin et al. 2004). The liver is also an important site of iron toxicity: hepatic fibrosis can occur early in childhood eventually leading to cirrhosis (Aldouri, Wonke et al. 1987), liver failure and hepatocellular carcinoma (Borgna-Pignatti, Rugolotto et al. 2004; Borgna-Pignatti, Garani et al. 2014). Hepatic complications are accelerated in the presence of chronic hepatitis C virus infection (Di Marco, Capra et al. 2008). There is good evidence that the majority of complications can be prevented if iron stores are maintained within a safe range. In some situations, reversal of tissue damage is possible if intensive iron chelation therapy is instituted and adhered to. This is well established for cardiac disease (Anderson, Westwood et al. 2004; Tanner, Galanello et al. 2008) and there are also some data on improvement or reversibility of endocrine dysfunction (Farmaki, Angelopoulos et al. 2006). The expectation is that well monitored and chelated patients will have a near normal life expectancy.

Assessment and monitoring of iron overload Transfusional iron loading Estimating current iron stores, and monitoring their trends with time are essential for evaluating the likely risks of morbidity and mortality, and for making informed clinical decisions regarding chelation therapy. This requires knowledge of the transfusion history, and of past and present iron chelation. The annual transfusion requirement can be expressed in ml/kg/year of pure red cells using the estimated haematocrit of the transfused blood available from the blood transfusion laboratory. Average daily transfusional iron loading (expressed as mg/kg/day), can be calculated assuming 1 ml of pure red cells contains 1.08 mg of iron (Cohen, Glimm et al. 2008). Patients whose transfusion iron loading is more than 0.3 mg/kg/day generally require higher doses of chelating agents to achieve negative iron balance (Cohen, Glimm et al. 2008). To assess the long-term effects of iron overload it is also necessary to know at what age chelation was started, and to ascertain the pattern of adherence to therapy and whether there have been periods of poor or absent chelation.

Serum ferritin (SF) SF levels are an indirect measure of transfusion iron loading. Values up to about 4000 μg/l reflect macrophage iron, whereas levels above 4000 μg/l also reflect hepatocyte damage (Brittenham, Cohen et al. 1993). Ferritin levels are elevated during intercurrent infections, chronic inflammatory conditions and chronic viral hepatitis, and this can lead to an overestimate of the degree of iron loading. Conversely, low levels may give false reassurance. Long-term mean 2016

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ferritin measurements in the range 500-1500 μg/l have been observed in some patients who have severe cardiac iron loading and left ventricular impairment (Tanner, Galanello et al. 2008). This is probably due to accumulation of iron in the myocardium either during periods of poor adherence to desferrioxamine (DFO), or in the case of older patients, delay in starting chelation. Low vitamin C (ascorbate) levels also cause low serum ferritin readings in the presence of significant iron overload. As such, SF should not be used as an indicator of cardiac iron concentration. SF and Iron chelation The interpretation of SF levels and trends in SF also depend upon the iron chelator drug. With DFO, persistently high levels (>2500μg/l) are associated with an increased risk of cardiac disease and death (Olivieri, Nathan et al. 1994), and levels maintained in the range 500-1500 μg/l over the long term carry a relatively low risk (Telfer, Prestcott et al. 2000; Borgna-Pignatti, Rugolotto et al. 2004). In the case of deferiprone (DFP) and deferasirox (DFX), levels fall concurrently with reductions of liver iron (Cappellini, Cohen et al. 2006; Pennell, Berdoukas et al. 2006; Tanner, Galanello et al. 2007). Ferritin levels fluctuate markedly, and a rise seen from one month to the next should not prompt an immediate change in therapy. Trends in SF apparent over a period of at least 3 months are a more reliable indicator for adjusting therapy.

Other serum markers of iron overload Iron is transported in the plasma predominantly bound to transferrin. Regular transfusion progressively overwhelms the normal body storage and transport mechanisms. As a result, transferrin quite quickly becomes fully saturated and non-transferrin bound iron (NTBI) appears in the plasma consisting of circulating iron not bound to transferrin, ferritin or heme. Labile plasma iron (LPI) is a fraction of NTBI which is redox-active and available for chelation. LPI can permeate cells and generate free radicals, which are thought to be the major cause of tissue damage in transfusion iron overload. LPI values have also been evaluated in different chelation regimes. In long-term chelated TM patients, 24 hour LPI is well controlled during long-term therapy with DFX or with daily sequential combination of DFP and DFO. During monotherapy with DFO infusions, levels increase after discontinuing the infusion. During standard DFP therapy, levels fluctuate during the day and increase overnight (Daar, Pathare et al. 2009; Porter, El-Alfy et al. 2016). Measurement of transferrin saturation (TSAT) is a routine biochemical test, and may be useful in assessing mild untreated iron overload. Measurements may be unreliable when chelators are present in the plasma, and are not informative in detecting changes when there is severe iron overload and fully saturated transferrin (Porter, El-Alfy et al. 2016). Various assays have been described which measure different components of NTBI. One reported method for LPI uses a fluorescent probe which measures redox-active iron, and the chelatable form is calculated as the proportion which is removed in the presence of excess DFO (Esposito, Breuer et al. 2003). Comparisons of methodologies have confirmed correlations with TSAT, but demonstrate significant differences in absolute values measured for LPI or NTBI (de Swart, Hendriks et al. 2016). In TM patients, LPI is detected once TSAT increases above 70% (Cabantchik, Breuer et al. 2005). One study has suggested that TSAT>90% can be used to predict LPI appearance in chelationnaïve TM children and this may be of value in deciding when to start chelation (Danjou, Cabantchik et al. 2014). A reduction in TSAT may also be an indication that chelation can be reduced or temporarily discontinued in patients whose SF and LIC values are below recommended limits, but there are no clinical trials evaluating this proposal.

Liver iron concentration (LIC) Liver biopsy Liver tissue obtained directly using a needle or intra-operative wedge biopsy can be analysed chemically for iron content. Histological examination of liver tissue also gives useful information about hepatic inflammation, fibrosis and cirrhosis. Liver biopsy was previously recommended as the most reliable means of assessing iron loading in children in order to decide on when to start DFO chelation (Olivieri and Brittenham 1997). However, biopsy LIC is invasive, and results show

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poor reproducibility, particularly if the biopsy is small or cirrhotic. The co-efficient of variation has been estimated at about 19% in non-diseased, and 40% in fibrotic, livers (Kreeftenberg, Koopman et al. 1984; Villeneuve, Bilodeau et al. 1996; Emond, Bronner et al. 1999). MRI methodologies Magnetic resonance imaging (MRI) can exploit the paramagnetic properties of iron to obtain a quantitative measurement of concentration in body tissues. MR scanning is non-invasive, allows averaging of LIC over a large volume of liver tissue, and is suitable for sequential assessment. All MRI-based methods require calibration against LIC measured by chemical analysis of liver tissue and are subject to variability, which may be increased with higher degrees of iron loading and hepatic fibrosis. Additional factors, such as hepatic fat content, may also play a role. This variability is probably less than for LIC determined from biopsy. Spin-echo (R2) and gradient echo (R2*) methods have been developed, refined and evaluated in various clinical settings over the past 15 years and both are now considered suitable for routine clinical use provided they are done using a standardised and validated protocol. R2 LIC (Ferriscan™) St Pierre and colleagues have developed an R2 scanning protocol and demonstrated a robust calibration curve of R2 against biopsy LIC, applicable to different iron loading conditions, patients on different chelation regimes, and to young children. The method has been commercialised under the trade name Ferriscan®, and electronic transfer of MR data to a centralised processing centre allows LIC to be calculated and reported in a standardised manner (St Pierre, Clark et al. 2005; St Pierre, El-Beshlawy et al. 2014), www.resonancehealth.com. R2* LIC The Royal Brompton group in the UK demonstrated a logarithmic relationship between R2* and LIC on liver biopsy as a proof of concept for development of myocardial iron estimation (Anderson, Holden et al. 2001). The technical details of the original methodology have been significantly improved by several groups, and re-calibrated against biopsy liver iron resulting in a more reliable estimation of LIC over the range of clinical values. These groups have produced different calibration curve compared to the original method (Wood, Enriquez et al. 2005; Hankins, McCarville et al. 2009; Garbowski, Carpenter et al. 2014). At present a consensus has not been reached on the standardisation of R2* methodology for routine clinical use. One recent study compared a modification of R2* LIC with R2 (Ferriscan®) (Garbowski, Carpenter et al. 2014). Although both methods showed a good linear relationship between LIC and MR parameter, the agreement of results between the two methods was inadequate over the range of clinically relevant values. This suggests that R2 and R2* have different sensitivities to different forms of storage iron in the liver, and that the methods cannot be used interchangeably. Optimal levels of LIC Determining the optimal range of LIC requires a balance between avoidance of iron toxicity and prevention of chelator-induced toxicity. Although normal LIC is 0.2-1.8 mg/g dry weight (dw), maintaining levels within the normal range may increase the risk of chelator toxicity, and the desired LIC range for a regularly transfused TM patient should probably be higher (Olivieri and Brittenham 1997). Clinical observations in genetic haemochromatosis suggest that levels between 3-7 mg/g dw - the range seen in heterozygotes - should not result in hepatic or endocrine toxicity (Olivieri and Brittenham 1997). Levels above 15 mg/g dw in thalassaemics on DFO have been associated with an increased risk of morbidity and mortality from iron overload (Brittenham, Griffith et al. 1994; Telfer, Prestcott et al. 2000).

Cardiac iron In iron loaded TM patients, myocardial tissue iron concentrations are usually less than in the liver. Assessment of cardiac iron overload by gradient-echo R2* MRI was initially developed at the Royal Brompton Hospital (Anderson, Holden et al. 2001). These sequences are particularly sensitive to magnetic properties of tissue iron, and are acquired over a short time span, so that motion artifacts from myocardial contraction can be minimised. The relationship between myocardial iron concentration (mg/g dry weight) and T2* was derived in a study of 12 post 2016

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mortem or explanted hearts from patients with iron overload. T2* is expressed in milliseconds: the higher the reading, the lower the cardiac iron. Cardiac T2* has been shown to be reproducible on different scanners, and made widely available for clinical use (Westwood, Anderson et al. 2003). An international panel recently recommended that myocardial T2* is assessed on 1.5 Tesla CMR, using single breath hold multi-echo sequence with image acquisition from the full-thickness short axis view of the intraventricular septum. Clinically validated software should be used for image analysis. More detailed technical aspects of myocardial iron assessment by T2* have been reviewed in the same document (Pennell, Udelson et al. 2013). Cardiac MRI is an excellent tool for measurement of ventricular size and performance. It has shown that normal left ventricular ejection fraction (LVEF) in TM patients is higher than in non thalassaemic controls (Westwood, Anderson et al. 2007). LV impairment becomes increasingly likely when T2* falls below 20 milliseconds (ms) (Anderson, Holden et al. 2001; Tanner, Galanello et al. 2006). Nearly all patients with clinical evidence of heart failure have a very low T2* ( 70%) of diabetes amongst older TM patients (> 40 yr), who develop atrial fibrillation. Whether this is a non-specific association, due to a more severe phenotype or to a specific role for diabetes, is unclear. However, when considering the possibility of AF in an older TM patient the co-existence of diabetes should increase suspicion. Thyroid and gonadotrophin deficiency The frequent co-existence of these endocrinopathies has not been examined independently as factors in the development of cardiovascular complications. Adrenal insufficiency Adrenal dysfunction may be a particular problem when managing severely ill TM patients. In the context of acute illness and severe heart failure, consideration should be made to providing adrenal support, even before formal proof of insufficiency is available.

Lifestyle Smoking It is not clear whether there are any specific interactions between smoking and the development of cardiovascular complications in the TM population but it is very unlikely that they are immune to the general deleterious effect of smoking on health. All patients should be given strong recommendations to stop smoking and appropriate support “to quit” should be offered. Sedentary lifestyle People with thalassaemia may have challenges in maintaining a healthy degree of physical exercise, due to associated bone and joint complications. Nevertheless they should be encouraged to maintain regular exercise within their capacity. In particular, reassurance needs to be provided that cardiovascular status is likely to be improved in the long term by a healthy active lifestyle. Diet and Lipids In this group of patients, often affected by hypotension, generic advice given to the general population regarding the limitation of salt intake may not be appropriate. The risk of arteriosclerosis also appears to be low in TM patients, so extreme diets, including low fat, need to be discouraged and a more holistic approach undertaken. By the same token, although it appears reasonable to offer prospective primary prevention therapy in the situation of abnormal lipid metabolism, there is no data to support this approach, particularly as people with thalassaemia appear to have an unexpectedly low incidence of arteriosclerotic heart disease. Efforts to encourage lifelong compliance with chelation and diabetic control should probably take precedence.

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Cardiovascular Investigations Clinical history and examination The insidious development of cardiac dysfunction can be difficult to detect, as symptoms are frequently non-specific. Exercise limitation, breathlessness, exhaustion are all symptoms frequently associated with anaemia. Changes in status are generally the key and mandate investigation. Chest pain and palpitations are relatively common, and may not always relate to clinically significant pathology, cardiac dysfunction or iron overload, but require investigation. There are no thalassaemia-specific cardiovascular features to be found on examination. However, it is common to encounter a low normal blood pressure, frequently with systolic BP < 100 mmHg and anaemia-associated, usually innocent, systolic murmurs at the base of the heart. Of particular importance is the appearance of changes in signs, particularly the development of indicators of cardiac failure or pulmonary hypertension. Clinical examination, including recording of pulse, blood pressure, oxygen saturation by pulse oximetry, and cardiovascular findings should be recorded at least at every annual review visit.

ECG and ambulatory recording A standard 12 lead ECG commonly shows non-specific abnormalities particularly of repolarisation (non-specific T-wave changes), but these are of unclear significance if longstanding. They are more common in patients with a history of severe iron overload, but are not a reliable indicator of current cardiovascular iron status. An early baseline ECG is important, to enable changes across time to be identified. The frequency of surveillance ECGs is dependent on individual circumstances, but a minimum of once every 2 years for completely stable, non-iron overloaded TM patients is useful to detect subtle but uncommon developments, such as conduction disturbance, QT prolongation, ventricular hypertrophy or RV overload. Annual ECGs, at least, should be obtained for those with iron overload, an abnormal baseline ECG and any patient with in-dwelling central venous catheters. As intermittent arrhythmias will frequently be missed on a standard ECG, ambulatory recordings need to be considered. The standard 24hr Holter monitor will miss many intermittent and potentially important abnormalities of rhythm and conduction. Longer term monitoring, using Holter recorders, newer patient activated recorders, adhesive patch ECGs and implantable loop recorders (ILR) need to be considered in individual cases. There is no clear indication at this time to embark on prospective arrhythmia surveillance in asymptomatic TM patients, with the exception of those who have suffered a neurological, or other possible embolic event, where silent atrial fibrillation must be excluded.

Echocardiography Echocardiography is the most practical means of regular long-term monitoring of ventricular size and function, and can be used for annual or more frequent follow up for myocardial iron toxicity, and in experienced hands can even identify patients at risk. Some cardiovascular complications, such as intra-cardiac thrombus may be detectable on echocardiography but undetectable by other imaging modalities, such as MRI scanning. Echocardiography remains the best method of detecting pulmonary hypertension and diastolic ventricular dysfunction, or restrictive physiology. The most frequently used parameter of ventricular function is the ejection fraction (EF) although this parameter alone cannot fully describe cardiac function. Echo EF has a coefficient of variation (CV) of 7% at best and is probably closer to 10% in general cardiology services. MRI values are better, probably closer to 5% (Grothues et al. 2002) and this lower CV is also associated with more contemporary echo techniques, including 3D volume analysis. More sophisticated measures of cardiac function, such as Tissue Doppler Imaging (TDI) and global longitudinal strain (GLS) have demonstrated their usefulness in TM and other cardiomyopathies, achieving greater sensitivity and specificity, particularly for detecting minor changes in function. It is particularly important to identify these early changes in this patient group, so that appropriate chelation treatment can be discussed.

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Table 17.1: Parameters for an adequate echocardiogram in TM population (E = essential, D = desirable) Parameter

Comment

E/D

Chamber dimensions

LV end-diastolic and end systolic; LA diameter or area; RV size

E

Ventricular systolic function; radial

SF; EF by Teicholz and by biplane analysis, modified Simpson’s; not “visual estimate”

E

Ventricular diastolic function

E/E’ plus other parameters

D

Tricuspid jet Vmax

To detect pulmonary hypertension; preferable to calculated PAsp: 3.0 m/s is abnormal. No TR jet in many cases, generally means normal R heart pressures.

E

Ventricular function, longitudinal

TAPSE, LV and RV; better by Tissue Doppler (TDI) Sa parameters

D

Strain imaging

Global longitudinal strain (GLS); likely to supplant EF for surveillance

D

3D Volume analysis

3D volumes and derived EF improve accuracy of surveillance; will supplant current methodology

D

Cardiac MRI The introduction of MRI for the detection of cardiac iron has transformed the management of patients with thalassaemia major. Prior to 2000, serum ferritin or liver biopsies were used to measure iron overload but these are inaccurate and do not always accurately reflect cardiac iron; the primary source of mortality. Over a decade of investigation, the T2* Cardiovascular Magnetic Resonance (CMR) technique was developed allowing an accurate non-invasive assessment of cardiac and liver iron burden (Anderson et al. 2001). T2* is one of the three fundamental tissue signal MRI rate constants. T2* measurements are derived from a single mid-ventricular short-axis slice. It is a robust, reliable method and has been validated histologically. Cardiac iron levels are inversely related to myocardial T2* values. Values of 20 ms or higher indicate absence of clinically important iron overload, lowest risk; 10 – 19 ms indicate mild to moderate cardiac iron, low risk of heart failure; < 10 ms: severe iron overload with substantial risk of immediate cardiac complications: heart failure risk rising from 14 – 30% within 1 year if 6 – 9 ms, and 50% risk of heart failure within 1 year if < 6 ms (Kirk et al., 2009) All patients receiving regular transfusions should have a quantitative tissue iron load assessment, by CMR scanning at the earliest possible opportunity, which for most TM patients is likely to be between 7 to 10 years. Repeat scanning every year in the most vulnerable danger period, as their care moves from the paediatric services to adult medicine is to be encouraged, with at least CMR, ECG and echocardiography. Thereafter the interval of surveillance should not exceed 2 years for well chelated individuals able to take their treatment but should be more frequent in patients having difficulties with treatment, or with abnormal baseline results, or suggestive cardiac symptoms. Investigations at less than 6-monthly intervals are unlikely to detect meaningful changes, the rate of iron removal being relatively slow in the heart. Appropriate CMR scanning intervals are: • T2* > 20 milliseconds – every 2 years • T2* 10 – 20 milliseconds – yearly • T2* < 10 milliseconds – 6 monthly In non-iron loaded patients a search must be made for alternative causes of ventricular function impairment. Echocardiography is more readily available for serial and frequent assessment of dimensions and function, with CMR being utilised more sparingly to confirm associated iron load changes.

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Clear communication with patients regarding CMR scans should clarify that scans are free from ionising radiation and repeated scanning poses no health risk. Patients sometimes find the MR scanner claustrophobic, and the nature of the machine should be explained to them before their appointment. If a patient has a pacemaker or other implanted device, confirmation that it has MRI compatible components will be required.

Nuclear Medicine Nuclear studies were used before the introduction of the T2* technique. Early left ventricular dysfunction could be detected using radionuclide cineangiography (MUGA scanning) during exercise in patients with thalassaemia. Nuclear medicine however requires the use of radioactive isotopes and this modality is no longer recommended for routine investigation.

Blood biomarkers Brain natruiretic peptide (BNP) is a serum biomarker for the presence of cardiac failure. It has not been shown to be helpful in the routine surveillance of the TM population, nor does it appear to give early warning of ventricular involvement or cardiac iron overload (Pennell, Udelson et al. 2013). In individual cases of established heart failure, measurement of BNP can help guide volaemic status and it may be useful in differentiating breathlessness due to pulmonary problems versus that due to cardiac failure.

Management of cardiovascular complications Arrhythmia A variety of arrhythmias have been described complicating thalassaemia. These are mostly tachycardias, but in inadequately chelated patients, bradycardia and heart block may be seen. The heart block will usually, but not always, respond to removal of myocardial iron. Pacemakers are rarely required, but if symptomatic bradycardia or heart block do not improve despite intensive chelation, the use of MRI compatible pacemakers is justified. Acute arrhythmia Ventricular tachycardia (VT) is a grave indicator of heart dysfunction, as in any form of cardiomyopathy, requiring urgent and expert assessment. It is almost uniquely a feature of severe myocardial iron overload in the TM population and usually responds intensification of chelation. VT is a medical emergency requiring admission to hospital and severe cardiac decompensation or non-responsive VT mandates the use of DC cardioversion to restore sinus rhythm as quickly as possible. Intra-venous continuous chelation with desferrioxamine (DFO) 50 – 60 mg/kg/ day should be started as soon as possible, with the early addition of oral treatment with deferiprone (DFP) 100 mg/kg/day in divided doses. Other therapies are dependent upon the response to chelation, but would include beta-blockers and amiodarone as well as normalisation of electrolyte disturbance, particularly potassium and magnesium. Consideration of device therapy, ICD, after the initial event, should be delayed until the response to chelation has been fully assessed. It will usually prevent further MRI scanning, a potentially serious problem for TM patients. Unlike virtually all other cardiomyopathies faced by cardiologists and EP physicians, VT in this group of patients can be considered a toxic manifestation of iron and its removal associated with minimal risk of further VT, unless there is evidence of irreparable damage to ventricular function. Atrial fibrillation (AF) may be the precipitating event that causes acute cardiac decompensation in severely iron-overloaded hearts. Under these circumstances, treatment should follow the principles outlined above for VT. Early consideration of DC cardioversion is advised. Chronic and late appearing arrhythmia Atrial arrhythmias, including atrial fibrillation (AF) do not always indicate severe cardiac iron toxicity and are increasingly evident in older cohorts of thalassaemia patients, even though they may have successfully chelated down their cardiac iron level decades previously.

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Atrial fibrillation may carry a higher risk of stroke than in age-matched non-thalassaemic individuals. This is especially true for those who have undergone splenectomy and for those with diabetes. All TM patients describing anything other than very infrequent, transient arrhythmia or palpitations need prolonged ECG monitoring for diagnosis and detection. Cardiac MR imaging, if not on recent record, should be repeated to establish if cardiac iron is present, in which case a suitable intensive chelation regimen should be started promptly. Medical management of arrhythmias is similar to non-thalassaemia patients. Beta-blockers and class I anti-arrhythmics appear to be safe and effective. Anti-coagulation (vitamin K antagonists, such as warfarin, or the newer Direct Oral Anti-Coagulants, such as dabigatran, apixaban or rivaroxaban) should be strongly considered for patients with a significant burden of AF. The standard CHADS-Vasc scoring system for stroke risk in AF should not be applied to TM patients. Ablation treatment for arrhythmia have been successfully used; it is very effective and often curative for atrial tachycardias (AT, atrial flutter), but less reliably successful for atrial fibrillation (AF). Nevertheless these techniques offer promise for severely symptomatic patients, particularly as these patients’ ability to tolerate adequate doses of beta-blockers or other anti-arrhythmic therapy may be limited by systemic hypotension.

Heart Failure (HF) Acute, decompensated HF The development of acute heart failure complicating thalassaemia is now thankfully rare, but still has a high immediate mortality risk, approaching 50%. This emphasises the importance of avoiding this complication by adherence to regular chelation, guided by CMR T2* measurements. Patients with a T2* 50% risk of developing heart failure within 12 months (Kirk et al. 2009). However, even with acute severe decompensated heart failure, restoration of completely normal ventricular function is possible with the intensive continuous chelation as described above for acute VT. The potential for complete reversibility of heart failure in TM may not be appreciated by clinicians who are not familiar with the management of these patients. Improvements in ventricular function assessed by echo or CMR precede demonstrable improvements in iron content measured by T2*. In addition to intravenous DFO (50 – 60 mg/kg/day) with oral DFP (≤100 mg/kg/day), grade IV heart failure patients should receive adrenocorticoid therapy, thiamine and electrolytes to maintain high normal values of serum K+ and Mg++. All efforts should be made to support the circulation, but care must be taken to ensure that intensivists are aware of the particular haemodynamic features of this patient group. Inotropic support must be used cautiously in these patients, who often improve on much lower central systemic blood pressures than seen in nonthalassaemia heart failure patients. Support should be continued long enough to allow adequate removal of the toxic iron accumulation, which may take days or weeks in some circumstances, particularly if renal function is impaired. Scrupulous attention to diabetic control and rapid treatment of associated arrhythmia is essential. As soon as practicable, the introduction of conventional heart failure medication, including ACE inhibitors or angiotensin receptor blockers with beta-blockers and aldosterone receptor blockers should be considered, (Pennell, Udelson et al. 2013), although conventional doses may not be tolerable because of low blood pressure. Although in non-thalassaemia heart failure these medications are prescribed for long term use, the length of time of exposure for the TM subgroup is not established. People are usually advised to avoid alcohol for at least a few months after an episode of acute heart failure. Chronic heart failure Although recovery of function with adequate chelation is the expected outcome of treatment of HF in TM, a number of patients have long term impaired ventricular function. In some this may be due to a coincidental dilated cardiomyopathy, unrelated to iron overload, or follow a viral myocarditis. Rarer diseases need to be excluded in any atypical presentations or inadequate responses to conventional approaches with chelation and HF medication. Valve disease is approached conventionally and successful heart surgery has been undertaken in TM patients.

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A more insidious condition, of diastolic heart failure, is increasingly seen in older patients with TM. This does not seem to be immediately associated with iron overload, but may be more common in individuals with a past history of heart failure. Sometimes termed heart failure with preserved ejection fraction (HFpEF), the features are of normal or mildly reduced EF, increased ventricular filling pressures, dilated atria and an increased propensity to AF. Symptoms are similar to heart failure with reduced ejection fraction (HFrEF), but the implications for prognosis are probably less severe, at least in the medium term. Features of congestion, with peripheral or pulmonary oedema, and the development of pulmonary hypertension in the long term are potential consequences of HFpEF, for which there is no specific therapy. Diuretics have a role, for symptom control, but must be used with caution. Despite the lack of evidence of efficacy most cardiologists also treat HFpEF with conventional HF treatments. Occasionally surveillance reveals progressive change in ventricular function, often not accompanied by symptoms. Under these circumstances CMR assessment for T2* (iron overload) should be undertaken as soon as possible and initiation of intensive chelation therapy begun. Consideration needs to be made whether conventional heart failure medication, such as betablockers, ACE inhibitors or angiotensin receptor blockers and aldosterone antagonists, should also be introduced at this stage; there is little to argue against this approach, which can be reviewed in subsequent clinic visits once improvement in cardiac function is achieved. Pulmonary hypertension (PHT) This is uncommon in thalassaemia major, but is a particular feature of untransfused patients. It is believed that intra-vascular haemolysis plays a major part in the development of pulmonary vascular endothelial dysfunction. Thus the emphasis in treatment has been to transfuse TI patients intensively if PHT is diagnosed. However, chronic pulmonary thrombo-embolism may contribute, so consideration should also be given to life-long anticoagulation. Once established, PHT carries a poor prognosis, with the development of right ventricular (RV) dilatation followed by RV dysfunction and failure, for which there are no adequate treatments available. There is some experience to support the use of phospho-diesterase 5 inhibitors (sildenafil, tadalafil) in the treatment of PHT. Individual patients should be referred to national pulmonary hypertension centres to be considered for more complex therapies, such as endothelin antagonists or phosphodiesterase inhibitors. Iatrogenic pulmonary hypertension has been observed in patients with indwelling central venous catheters (IVC), due to undetected chronic pulmonary thromboembolism. There are instances of successful use of surgical pulmonary thromboembolectomy to treat these patients, but this high risk surgical intervention must be avoided if possible. This experience has led to the recommendation for full anti-coagulation of all patients fitted with IVC devices, usually with vitamin K antagonists.

Management of the cardiovascular system in pregnancy Fitness to consider pregnancy Fertility is commonly reduced in patients with thalassaemia due to iron loading in the anterior pituitary gland, and will often require assisted reproductive methods to successfully conceive. Thalassaemia poses an increased risk to both mother and fetus, and the risk of cardiac complications ranges from 1% to 15% (Pennell, Udelson et al. 2013). The RCOG recommend review by a cardiologist with expertise in thalassaemia during the planning stages (Royal College of Obstetricians & Gynaecologists 2014). A thorough assessment is required to determine the cardiac status prior to embarking on pregnancy and this must include ECG, transthoracic echocardiogram for assessment of longitudinal and radial function, and valvular assessment, and cardiovascular MRI for cardiac iron quantification. It is recommended cardiac T2* values should be above 20ms, indicating no significant iron loading and left ventricular function should be normal (EF > 65%). Reduced LV function is a relative contraindication to pregnancy. T2* values 20 ms on last assessment

E

– Poorly chelated patient, without heart failure or impaired LV function, AND patients recovered from an episode of acute heart failure AND those with impaired LV but no symptoms – see Table 17.3

Table 17.3: Assessment schedule for poorly chelated patient, without heart failure or impaired LV function, AND patients recovered from an episode of acute heart failure AND those with impaired LV but no symptoms. Assessment

Surveillance interval

Comment

E/D

Clinical cardiology visit and exam

Immediate, then 3 to 6 monthly

Dependent on severity of T2*; 3 monthly if < 6 ms

ECG

At each visit

E

ECHO

6 monthly

E

MRI

6 monthly if T2* < 10 ms Yearly if T2* < 20 ms

E

Unlikely to be helpful to repeat MRI at less than 6 month intervals

E

 Particular vigilance is required before and during pregnancy – see Table 17.4

Table 17.4: Assessment schedule during pregnancy Assessment

First visit

Surveillance

Comment

Clinical cardiology visit and exam

When planning pregnancy

Pre-conception At ~ 12/40 gestation At 28/40 gestation 3 months post delivery

If abnormalities on testing, or significant symptoms, may need more intensive monitoring

E/D E D D

ECG

First visit

D

ECHO

Every visit

E

MRI

Pre-conception and postdelivery visits

E

 Echocardiographic assessment must be undertaken and reported by an operator experienced in cardiac assessments in thalassaemia. A minimum data set, detailed in table 17.1, should be recorded each time.  Findings of any cardiac iron on T2*, or impairment of cardiac function, or new arrhythmia should lead to an early review of the patient’s chelation regimen, to ensure it is optimised in regard to reducing myocardial iron (see chapter 10: Monitoring and Management of Iron Load ).  Patients with ventricular arrhythmias or clinical cardiac failure must be admitted to hospital, and started on continuous intravenous desferrioxamine 50-60 mg/kg/day, with oral

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deferiprone 100 mg/kg /day in three divided doses being introduced as soon as possible, in the absence of any contraindications.  Patients with ventricular arrhythmias or clinical heart failure must be managed in liaison with the SHC, and preferably transferred for in-patient management there.  Patients found to have pulmonary hypertension must be managed in conjunction with the most convenient national pulmonary hypertension service team.  Patients who have an in-dwelling venous device should be fully anti-coagulated.  Patients with atrial fibrillation, including paroxysmal, must receive anti-coagulation therapy.  Patients who have suffered a neurological, or other possible embolic event must be investigated for silent or paroxysmal atrial fibrillation.

Recommendations • Lifestyle factors likely to affect cardiovascular health should be explored, and patient strongly advised to undertake physical exercise, and not to smoke cigarettes. • Co-morbidities such as diabetes mellitus and hypothyroidism should be optimally managed so as not to contribute to cardiovascular morbidity. • Repetition of T2* measurements within 6 months of a previous measurement is not recommended. • A T2* > 20ms and EF > 65% is recommended prior to embarking on pregnancy.

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18: Management of Impaired Glucose Tolerance and Diabetes Mellitus “I am being treated for diabetes but I would like to see a specialist doctor.” “We need better focus on preventative medicine rather than fixing once broken e.g. osteoporosis & diabetes.”

Aims To optimise quality of life and prevent diabetes complications and premature death by: • encouraging meticulous adherence to iron chelation medication to lower the risk of developing diabetes, as well as other complications, and possibly to improve or normalise glucose metabolism if impaired. • early diagnosis of impaired glucose regulation and diabetes. • preventing the progression of impaired glucose regulation to diabetes. • optimising glycaemic control and other cardiovascular risk factors. • early detection and treatment of diabetic complications. • supporting patient self-management.

Standards  A paediatric and adult consultant diabetologist should be identified for each Specialist Haemoglobinopathy Centre.  Patients should be checked annually for impaired glucose regulation and diabetes from puberty, or from age of 10 years if there is a family history of diabetes.  Patients with diabetes should have a full annual diabetes review, including glycaemic control, cardiovascular risk factors, diabetic complications and sexual health.  Patients with diabetes should have access to a clinical health psychologist with experience in diabetes management.

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Background Impaired glucose regulation and diabetes mellitus are common and significant complications of thalassaemia. In adult patients attending a UK thalassaemia service, around 20% have impaired glucose regulation and up to 41% have diabetes (Ang et al. 2014). The main aetiological factor is transfusional iron overload which damages pancreatic β-cells, reducing insulin secretion. The other key factors for some patients are insulin resistance secondary to liver disease, and hepatitis C virus infection affecting glucose metabolism (Mowla et al. 2004). Risk factors for diabetes also include poor compliance with chelation therapy or advanced age at onset of chelation (Gamberini et al. 2004), increasing patient age, average serum ferritin over 10 years > 1250 μg/l, and myocardial T2 < 20 ms (Ang et al. 2014). In addition, with the global pandemic of diabetes, patients can develop type 1 or type 2 diabetes independently of their thalassaemia. Impaired glucose regulation and diabetes must be detected early to allow prompt treatment of hyperglycaemia and intensification of iron chelation therapy. Very intensive combined chelation can improve or normalise glucose metabolism in patients with impaired glucose regulation or non-insulin dependent diabetes, mainly through marked increase of insulin secretion (Farmaki et al. 2006, Farmaki et al. 2010). Intensive chelation can prevent progression to frank diabetes. Screening is with the oral glucose tolerance test, OGTT, which includes measurement of fasting plasma glucose (FPG) and plasma glucose 2 hours after oral ingestion of 75 gram glucose. According to the recommendations of the World Health Organisation (WHO/IDF 2006), results are interpreted as following: A. Fasting Plasma Glucose: i. FPG ≤ 6.0 mmol/l = Normal ii. FPG 6.1 – 6.9 mmol/l = Impaired Fasting Glycaemia (IFG) iii. FPG ≥ 7.0 mmol/l = Diabetes B. 2 Hour Plasma Glucose: i. 2-hour plasma glucose < 7.8 mmol/l = Normal ii. 2-hour plasma glucose 7.8 – 11.0 mmol/l = Impaired Glucose Tolerance (IGT) iii. 2-hour plasma glucose ≥ 11.1 mmol/l = Diabetes. If diabetes develops, a critical aim of care must be prevention, early detection and management of diabetic complications, including macrovascular complications (cardiovascular disease, cerebrovascular disease, peripheral vascular disease) and microvascular complications (diabetic retinopathy, nephropathy, neuropathy and erectile dysfunction). These complications can cause major patient morbidity and mortality and account in general for 80% of direct patient care costs in the UK. In patients with thalassaemia and diabetes, the prevalence of diabetic nephropathy is 13 – 55% (Tzoulis et al. 2014; Loebstein et al. 1998) and of diabetic retinopathy 13-26% (Tzoulis et al. 2014; Incorvaia et al. 1998). Macrovascular disease is uncommon, but is expected to increase as the life expectancy of patients with thalassaemia rises. Further, diabetes significantly increases the risk for cardiac complications, heart failure, hyperkinetic arrhythmias and myocardial fibrosis in patients with thalassaemia (Pepe et al. 2013). Living with diabetes and thalassaemia can have a major psychological effect, with feelings of treatment burden, being different, dependence, damage, anxiety and impact on daily life. Healthcare professionals need to be able to support their patients to manage their diabetes and enable patients to apply self-management skills to lead a full and rich life.

Requirements  All non-diabetic patients should be screened with Oral Glucose Tolerance Test (OGTT) and fructosamine annually from puberty or from the age of 10 years if there is a family history of diabetes.  In patients with impaired glucose regulation (IFG/IGT) or non-insulin treated diabetes, iron chelation therapy should be intensified, with consideration given to using combination chelation regimens, aiming to normalise the iron load as judged by cardiac and hepatic magnetic resonance imaging.

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 Patients with evidence of diabetes must be referred to the nominated consultant diabetologist in each Specialist Centre for further evaluation and treatment guidance, and their management kept under regular review by the specialist diabetes team. This is essential to provide adequate care for complex patients.  Overall glycaemic control should be monitored using fructosamine levels. Fructosamine is a circulating glycated protein which measures overall glucose control in the previous 2 – 3 weeks. Normal ranges vary in different laboratories but are generally around 205 – 285 μmol/l. HbA1c or glycated haemoglobin should be avoided in thalassaemia as it is unreliable after transfusion. Patients with impaired glucose regulation (IFG/IGT) should have fructosamine measured every 6 months to identify trends in glycaemic control, aiming to keep their fructosamine levels ≤ 325 μmol/l. Patients diagnosed with diabetes should have fructosamine measured every 3 months.  Any patient with symptoms of hyperglycaemia (e.g. thirst, polyuria, polydipsia, candida infections) should have urgent measurement of random plasma glucose and fructosamine. If random plasma glucose ≥ 11.1 mmol/l, which is diagnostic of diabetes, then blood or urinary ketones should be measured to exclude diabetic ketoacidosis.  Patients with diabetes who are acutely unwell and who are hyperglycaemic (plasma glucose > 12 mmol/l) should have blood or urinary ketones measured to exclude diabetic ketoacidosis.  Patients with diabetes should test capillary blood glucose at home in order to monitor glycaemic control and identify hypoglycaemia or severe hyperglycaemia. The frequency of monitoring depends mainly on their treatment, with increased frequency needed especially in patients on insulin.  Patients with mild to moderate hyperglycaemia should be treated with antidiabetic drugs. The choice of agent should be individualised and depends on the balance of impaired insulin secretion versus insulin resistance and on the patient’s co-morbidities. There is very limited data on the efficacy and safety of antidiabetic drugs in patients with thalassaemia. Metformin is the first line drug of choice except in patients with significant chronic kidney disease (eGFR < 30 ml/min), acute heart failure or acute respiratory failure. The choice of second line agent must be personalised. There are currently 5 classes of antidiabetic drugs, some of which are associated with weight loss and low rates of hypoglycaemia.  Patients with severe hyperglycaemia or worsening glycaemia on multiple oral antidiabetic drugs, should be treated with insulin. Severely insulin deficient patients should be considered for a multiple daily injection (MDI) or a basal-bolus insulin regimen, which contains slow-acting basal background insulin administered usually once a day and rapid-acting insulin taken with each meal.  Patients must have further diabetes specialist input in specific situations requiring excellent glycaemic control, including pre-conception, pregnancy and surgery.  Patients with diabetes must be regularly assessed, at least once a year, for other endocrinopathies, as they are at high risk of hypogonadism, hypothyroidism, hypoparathyroidism and bone thinning.

Recommendations • Patients with impaired glucose regulation or diabetes should be encouraged to undertake 150 minute of moderate-intensity activity per week which accelerates the heart rate (such as brisk walking). This can be taken in 10 minute bouts (NICE 2012). • Overweight patients with impaired glucose regulation or diabetes should be encouraged and supported to make lifestyle changes in diet and exercise, aiming to lose 5 – 10% of weight per year to reach a body mass index (BMI) < 25 kg/m2 or 16mg/g dw of liver tissue). However, this observation was made over five years of follow-up in young patients, and progression to fibrosis may be more rapid in adult patients (Angelucci et al. 2002). In general, liver iron levels should be kept low irrespective of concurrent viral hepatitis, and it is advisable to maintain levels in the lower part of the range of 3 – 7 mg/g dw. MRI assessment of liver iron concentration enables monitoring of liver iron levels without the need for serial biopsies and is considered less subject to variability than analysis of liver biopsy samples (Anderson et al. 2001; St Pierre et al. 2005; Wood et al. 2005). Non-invasive assessment of liver fibrosis using Fibroscan® may be helpful in assessing liver disease in thalassaemia, but further validation is required. Liver biopsy remains the only modality able to provide a histopathological diagnosis, but non-invasive tests of liver fibrosis should be considered for assessment of liver fibrosis if histological examination of the liver parenchyma is not essential. Biopsy should be reserved for the investigation of complex liver pathology and for the staging of liver fibrosis when clinical signs and non-invasive assessment are in conflict or equivocal.

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Elevations of transaminase levels are relatively common in patients receiving deferiprone, particularly in patients with HCV infection, but these changes are usually mild and nonprogressive, and rarely of sufficient severity to discontinue treatment (Ceci et al. 2002; Cohen, Galanello, Piga, De Sanctis and Tricta 2003). One small study of hepatic histology showed progression of hepatic fibrosis in 5 out of 14 patients treated with deferiprone for a median of 2.3 years (Olivieri et al. 1998). Four of these five patients were infected with hepatitis C. Subsequent studies were unable to confirm an association between treatment with deferiprone and progression to liver fibrosis, and later publications suggest that the fibrosis was more related to hepatic iron loading in the presence of hepatitis C infection (Maggio et al. 2002; Tondury, Zimmermann, Nielsen and Hirt 1998; Wanless et al. 2002). Elevated serum transaminase levels are common in patients treated with deferasirox but the association with drug therapy is not always clear. In the Phase III one year study and 5 year follow-up, approximately 1% of patients had confirmed elevations of ALT > 10 × upper limit of normal (Cappellini et al. 2011) and drug-induced liver damage is an infrequent but important adverse reaction reported in association with deferasirox therapy (Cappellini et al. 2006). There is histological evidence that liver fibrosis scores improve in patients on deferasirox even in the absence of changes in the liver iron (Deugnier et al. 2011). Liver function tests should be checked at baseline in duplicate, two weekly for the first month or after increasing dose, and thereafter monthly. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, the medication should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered.

Lifestyle and other factors Iron overload alone in the absence of hepatitis infections or chelation drugs results in raised transaminase levels (Angelucci et al. 2000; Jensen, Jensen, Christensen, Nielsen and Ellegaard 2003) and this should be taken into account when monitoring iron chelation side effects. Patients with thalassemia are still susceptible to liver disease from non-transfusion, non-infective and non-drug related causes. Underlying liver problems are worsened by the impact of excess alcohol use. Patients should be advised to use alcohol within the national gender based guidelines limits and to avoid binge drinking. Non-Alcoholic Fatty Liver Disease (NAFLD) is common in both adults and children ("EASL–EASD– EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease" 2016). NAFLD can result in iron overload in non thalassaemic patients and this is known as dysmetabolic iron overload. NAFLD results in liver damage due to non-alcoholic steatohepatitis. Patients with thalassaemia who may be at risk of this complication as a consequence of obesity should be given life style advice and referred to dieticians and hepatologists for appropriate advice.

Requirements  A hepatologist should be designated for each thalassaemia Specialist Centre.  Liver function tests and serum ferritin should be monitored at least every 3 months in patients on desferrioxamine and monthly in patients receiving oral chelation drugs.  Liver iron level should be maintained between 3 – 7 mg/g dw, aiming towards the lower end of the range. Assessments of liver iron should be by MRI (R2 or T2*) rather than liver biopsy.  Serological tests to monitor for viral hepatitis (anti–HCV, HBsAg, anti HB core ab) should be done every year. Adequate protection from hepatitis B virus should be ensured by a full course of vaccination initiated before the first transfusion or as soon as possible after it, and then by serial monitoring of anti-HBs ab titre and ‘booster’ vaccination as needed. Hepatitis A immunisation, a second dose 6 – 12 months after the first, should also be offered.  Patients with active hepatitis C infection (HCV RNA positive) or chronic active hepatitis B should be referred to the designated hepatologist for further virological studies (genotype, quantitation of viral load), assessment of liver fibrosis and decisions about management. Antiviral therapy is recommended in all patients with HCV viraemia. 2016

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 Patients with unexplained abnormalities of liver function tests should have a detailed drug and alcohol history, and be investigated promptly.  Patients with a history of excess alcohol use should be supported with regular advice on safe consumption and carefully monitored for development of alcoholic liver disease.  Patients with established cirrhosis should be reviewed regularly, by the designated hepatologist. Surveillance for hepatocellular carcinoma (measurement of alpha fetoprotein, liver ultrasound or cross-sectional abdominal imaging by MRI or CT) should be done every 6 months. Surveillance for oesophageal varices should be undertaken at the time of diagnosis of cirrhosis and every 2-3 years thereafter. If varices are detected they should be treated by a specialist hepatologist.

Recommendations • Patients should be given regular information about avoidance of liver disease, and on how to recognise clinical signs of liver disease. This could be part of the role of the specialist nurse. • Patients with deranged liver function tests and evidence to suggest Non Alcoholic Steatohepatitis or NAFLD should be given appropriate lifestyle and dietary advice management by a specialist with an interest in NAFDL.

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21: Management of Dental Problems “My local dentist is scared to treat me because I have thalassaemia and my hospital has no specialist service so where does that leave me?”

Aims To improve awareness of the potential dental and orofacial manifestations of thalassaemia. To ensure the appropriate pathways of dental care are in place, including prevention and the timely management of dental infections. To outline the dental implications in relation to the use of bisphosphonates in patients with thalassaemia.

Standards  Adequate red cell transfusion in children with thalassaemia should be sufficient to prevent the development of marrow overgrowth and facial bone changes, and some of the associated dental problems.  All patients should access regular dental care to prevent oral infection and manage the potential orofacial features of thalassaemia.  Patients presenting with acute dental infections/abscesses should receive urgent dental care and antimicrobial therapy as required.  Close liaison with the haematology team is required to determine the potential complications when delivering invasive dental treatment, and to put measures in place to reduce risk.  All patients should ideally have a comprehensive dental assessment with their local dentist prior to the commencement of bisphosphonate therapy to ensure that they are as dentally fit as feasible.

Background In the United Kingdom, as the prevalence of thalassaemia is patchy, many dentists may not have experience in treating a patient with the condition. This can impact on access to dental care and lead to problems with oral health for people with thalassaemia. It is well recognised that oral health has an important role in general health and well-being of individuals, and impacts significantly on the quality of life (Public Health England 2014c). Improving the knowledge of the dental and oral manifestations of thalassaemia is key to removing these barriers. Patients with thalassaemia should be encouraged to register with their local primary care general dental services at an early age so that preventative regimes can be put in place and regular care provided. Occasionally, patients may have multiple associated medical comorbidities which increase risk and require special adaptations to be put in place. In these cases, regular care within specialised services such as paediatric dentistry services or primary care based Special Care Dentistry services may be more appropriate. Hospital based Special Care Dentistry services also exist but are limited. They provide care for the most complex patients, particularly those who may require surgical intervention or dental extractions. They do not usually provide continuing care; on completion of treatment patients 2016

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are discharged to the primary dental services for regular review. Occasionally referral to hospital based Oral Surgery/Maxillofacial Surgery services may be required.

Oro-Facial Manifestations of Thalassaemia Many orofacial features have been described in thalassaemia, the extent of the changes depends on the severity of the anaemia, the patient's age, the duration of the clinical symptoms, and the timing of blood transfusion especially when transfusion is started late or is less intensive than recommended. In addition to thalassaemia major patients, non-transfusion-dependent patients are at risk.

Facial bones Bone marrow hyperplasia may result in malformation/enlargement of the facial bones, including the maxilla and mandible. This is usually more significant in the upper jaw, resulting in a characteristic appearance with prominent high cheekbones and relatively smaller lower facial bones. Bone marrow overgrowth may also result in a reduction in the size of the maxillary sinuses and nasal obstruction Where there is misalignment of teeth due to maxillary expansion, orthodontic treatment or cosmetic dentistry may be required to correct alignment. Orthodontic treatment can be more complex due to the hypercellular nature of the bone, short roots, and changes in dental arch parameters. Where teeth have been lost, the dimension of the dental arch can slowly expand making dentures feel tight and uncomfortable, causing ulceration.

Teeth Changes in the jaw dimension may also result in spacing of the upper teeth and rotation or forward drift of the upper front teeth. Delayed dental development / eruption may occur. The colour of the permanent teeth can be dark in patients with thalassaemia because of progressive iron accumulation within the tooth tissue as it is forming. Where there is misalignment of teeth due to maxillary expansion, orthodontic treatment or cosmetic dentistry may be required to correct alignment but dentists need to be aware that the result, as with dentures, may not be stable and requires close review. Although it has been suggested these patients may also have an increased risk of dental caries the evidence is not conclusive and there may be geographical variability in terms of access to dental care, which may impact on the findings.

Soft tissues of the mouth Oral ulceration and burning tongue may be present secondary to chronic anaemia. Iron deposition in the parotid glands can result in painful facial swelling but is rare. Necrotising stomatitis, possibly linked to agranulocytosis due to deferiprone, has also been described (Tewari et al. 2009).

Radiographic appearance of the facial bone and teeth The maxillary sinuses may be reduced in size. Thinness of the cortical bone, absence of the inferior dental canal and a ‘chicken wire’ appearance of the lower jaw are often observed (Hazza’a and Al-Jamal 2006). The roots of the teeth may be short and slender with the lamina dura (bundle bone around the tooth) appearing faint/attenuated.

Co-morbidities that may impact on dental care Individuals with thalassaemia may have multiple secondary effects of their disorder. These can impact on the delivery of dental care:

Chronic anaemia Dental care should be adapted to their tolerance of the planned procedure on the day of treatment.

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Infections Iron overload and splenectomy both increase the risk of infection (Wang et al. 2003). Multiple immune abnormalities (Vento et al. 2006), defective neutrophil and macrophage chemotaxis, and increased oral Candida albicans colonisation (Hazza et al. 2010) have been noted in patients with thalassaemia. Certain organisms are particularly common causes of dental infection in thalassaemia major; for example Klebsiella dental infections can act as a source of generalised septicaemia (Sarma 2007), which can be serious or fatal if not managed quickly.

Recurrent transfusions Prior to screening of blood products, people with thalassaemia were at increased risk of infection with hepatitis viruses and human immunodeficiency virus. Appropriate cross-infection protocols should be in place when providing care. In the case of associated hepatic disease / liver cirrhosis, caution must be used when prescribing medication.

Iron overload and consequent deposition in tissues Iron accumulation in cardiac, endocrine and hepatic tissues is well documented for patients with thalassemia major. Insulin dependent diabetes mellitus and cardiac iron overload are common. Patients may be receiving anti-dysrrhythmics and occasionally anticoagulation if they have intermittent atrial fibrillation or indwelling intravenous devices. Although many patients are asymptomatic despite cardiac iron overload, cardiac symptoms or complications may develop when they are anxious or undergoing a stressful dental procedure. Dentists need to be aware of the degree of cardiac involvement in an individual patient and implement appropriate precautions.

Bisphosphonates (BPs) and osteonecrosis of the jaw (ONJ) Bisphosphonates have been commonly used in thalassaemia patients for bone thinning, and cases of ONJ have recently been reported (Chatterjee et al. 2014). ONJ is characterised by transmucosal exposure of necrotic bone often triggered by surgical trauma such as dental extractions. The incidence of ONJ is higher with more potent intravenous BPs, ranging between 2% and 28%, with the majority of studies suggesting an incidence of 5-8% (< 10%). These studies however are in patients with different underlying conditions, predominantly myeloma or other malignancies. Incidence is time-dependent and dose-dependent, with the time to onset ranging from 4 to 120 months. The incidence of ONJ associated with oral BP is lower and is generally accepted to be less than 1% (Fedele et al. 2009). Incidence is again time-dependent and dosedependent, with the time to onset ranging from 3 to 10 years. There is currently no clear evidence for the efficacy of any intervention to manage ONJ; in the case of non-vital teeth/dental abscesses, root canal treatment should be considered to try and stabilise the infection, although where this is not possible, dental extractions are unavoidable. There is no evidence supporting the discontinuation of bisphosphonates temporarily as the drugs persist in the skeletal tissues for years. There is also no conclusive evidence supporting the use of antibiotics or topical antiseptic prophylaxis in reducing the risk of ONJ (Fedele et al. 2009).

Depression Lifelong adherence to a complicated medical regimen can potentially impact on the emotional functioning of patients with thalassaemia. This can impact on patient motivation and ability to accept dental intervention (Mednick et al. 2010).

Requirements  Dental care should be delivered as a coordinated team approach, ensuring close liaison with the paediatrician or haematologist. This will help to identify and manage the risk factors associated with thalassaemia and the potential associated co-morbidities. The appropriate setting for any given dental treatment, namely primary or secondary (hospital-based) care can then be determined.  Where dental infection is present, it should be managed early and aggressively. 2016

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 Patients, especially those who have had the spleen removed, are at increased risk of infection following any dental procedures associated with bacteraemia, including extractions or scaling. but oral co-amoxiclav, a dose before the procedure and continuing at 625 mg three times daily for 48 hours after, is usually given.  If sedation or GA is planned, close liaison with the haematology team is required – this will allow transfusion to be arranged and the haemoglobin to be optimised. Inhalation sedation is preferable to intravenous sedation but may not be sufficient to enable the delivery of a longer/more complex treatment, particularly when the patient is very anxious.  Anaesthetists should also be made aware of any additional cardiac, liver and/or renal complications.  All patients should have a comprehensive dental assessment with their local dentist prior to starting bisphosphonate therapy to ensure that they are as dentally fit as feasible. To minimise the risk of osteonecrosis of the jaw, emphasis is on reduction of mucosal trauma and avoiding dental extraction where possible. Preventive dental advice should be given, emphasising the importance of reporting any symptoms such as loose teeth, pain, or swelling, as soon as possible.

Recommendations • For all patients with thalassaemia receiving regular transfusions, invasive dental care should be delivered as soon as possible after a planned transfusion, as the patient’s haemoglobin will be optimal. • Individuals with thalassaemia should have access to early, regular and preventive dental care. This will help reduce the impact of any associated oral features and allow dental development to be monitored. This should include preventive oral care, including fluoride application / prescription, fissure sealants, and dietary advice. • Comprehensive oral assessment age 12-13 will enable planning for/prevention of difficulties from overcrowding/misplaced teeth • Although there is a theoretical risk associated with local anaesthetic containing adrenaline (may lead to impairment of local circulation), this is used routinely for patients with thalassaemia without reported problems. • If maxillofacial surgery is planned for managing severe facial deformity associated with bone marrow expansion due to thalassaemia, careful consideration should be given to the medical and surgical risks, including the risk of more extensive bleeding from the hyper-vascular bone. (Park 2012) • If a patient has spontaneous or chronic bone exposure, referral to an oral surgery/oral and maxillofacial surgery specialist should be considered. When a patient is already on bisphosphonates and a dental extraction is unavoidable, straightforward extractions can be undertaken in primary care, although a second opinion can be sought when necessary. Surgical extractions should be undertaken by a specialist in oral surgery/maxillofacial surgeon. All patients should be advised of the risk of osteonecrosis of the bone pre-operatively and closely monitored post-operatively.

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22: Patients Previously Treated Outside the UK “People born in the UK take the medical system for granted, they don’t know how it feels to choose between buying food and going to hospital.” "We left a very comfortable life behind us for the sake of our 2 children who have thalassaemia. When I arrived in the UK I had never cooked a meal or cleaned my own house. My children are young adults now; but all the children we used to know from the hospital back home are dead."

Aims To ensure that patients starting, or returning, to use thalassaemia services in the UK can be assessed thoroughly at the outset, and start receiving care without delay. To ensure that patients and their families have a proper understanding of the condition and any complications. To address any unidentified or unmanaged problems. To ensure the person and family is introduced and integrated into local continuing care arrangements.

Standards  Children and adults who have been receiving treatment outside the UK will be seen, as soon as possible after they arrive, at an established Specialist Haemoglobinopathy Centre for a thorough assessment.  Transfusion treatment will be re-started without delay.  Any complications which may have developed will be detected and discussed with the individual and family and management plans put in place.

Background Thalassaemia services in many countries are of the highest quality and it is unlikely that a patient previously managed in, for example, Italy will have undetected problems. However, in some lower resource countries blood supplies may be erratic, screening of donor units may not be complete, or iron chelation may be unaffordable. It is possible therefore that the patient may have problems or complications of which they are unaware and/or which are untreated. Optimising transfusion and chelation treatment regimens, and actively managing any complications which have not been recognised to date, are likely to improve well-being and reduce morbidity and mortality. Patients who have recently arrived in the UK may present to A&E with anaemia or infection, may be referred by their GP or may make contact through the local support organisation or another patient. It is necessary to make an early appointment, to establish in the first instance when their next transfusion is due, and to start to make an overall assessment of their condition and its

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treatment. They may arrive with a full understanding about their condition, and plentiful documentation about their management to date, or they may have very little or none. Their initial assessment will include a full medical history covering: • age at diagnosis • age at first transfusion • transfusion history including transfusion reactions • chelation treatment, current and previous, including frequency, doses, route and any chelator intolerances or complications • any co-incident diagnoses • any other current medication • developmental history including puberty if of relevant age • surgical procedures, in particular splenectomy • complications from iron overload including cardiac failure, dysrhythmia and endocrinopathies: diabetes, hypothyroidism, hypoparathyroidism or hypogonadism • history of bone problems such as fractures and treatment for osteoporosis. The results of any investigations they are aware of should be explored – including haematology, biochemistry, virology, and any recent MR iron quantitation of the heart/liver, and where the tests were done. A family history is important for general clinical assessment, and will help elucidate whether other family members should be screened for thalassaemia. Patients should have a full medical examination, recording height (sitting and standing), weight, presence of thalassaemic facies or dental problems, signs of cardiac failure, the presence of an enlarged liver or spleen, surgical scars, stigmata of chronic liver disease, stage of pubertal development and any clinical signs suggesting endocrinopathy.

Requirements  Any newly arriving patient should be offered an early review with the team at the most convenient specialist Centre, with appropriate translation services available if needed. This will include a full discussion of their condition from the time of diagnosis, and previous and current treatment regimens, together with the results of any investigations of which they are aware, and a comprehensive medical examination.  Baseline investigations should be discussed with the patient and with their consent the assessments listed in Table 22.1 undertaken.  An early review visit should be planned to discuss the results of these investigations and any necessary treatment changes.  If hepatitis B non-immune, vaccination should be recommended and started as soon as possible.  It should be decided, and carefully discussed with the patient and family, what the recommended arrangements for continuing care will be: either at the local clinic with review visits at the Specialist Centre, or wholly at the Specialist Centre depending on proximity.  The family should be introduced to their key contact(s), and contact numbers exchanged.

Recommendations  The patient/family should be given written information about the services, and how to make contact as needed, in or out of hours.  A ‘first clinic visit checklist’ should be completed.  As soon as possible they should be taken to visit the transfusion unit which they will be attending, and meet the staff there. If possible they should be put in touch with some other patients and families.  They should be given contact details for any local support groups or organisations and for the UK Thalassaemia Society.

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Table 22.1: Baseline investigations and assessments FBC, blood film, haemoglobin HPLC (although may not be informative if recently transfused; family study may help) Serum or plasma ferritin assay

Immediate investigations

Blood group and antibody screen. Red cell genotyping, offered through the NHSBT. Hepatitis B and C serology to include Hep B surface antibody titre. HIV serology preceded by pre-test counselling. Full renal, liver, bone, sex hormone profiles, TFTs, random glucose, fructosamine if diabetic, PTH, vitamin D level, G6PD level. Globin genotyping (α and β globin genotype, -158 Gγ Xmn1 C→T polymorphism). Parental samples may be informative. Glucose tolerance test if not established diabetes mellitus

Semi urgent investigations

Abdominal and pelvic ultrasound to assess for gallstones, liver fibrosis or cirrhosis, spleen size and renal tract pathology (renal stones) and uterine/ovarian tissue in females Cardiac T2* Liver iron quantification using T2* or R2 DXA scan Audiology Ophthalmology Cardiac review

Other specialist assessments and clinical reviews

If diabetic, specialist diabetic clinic If impaired glucose tolerance, dietician and diabetes nurse review If other endocrinopathies, endocrine clinic If hepatitis B antigen or C antibody positive, hepatology clinic Patient and family members should be offered genetic counselling, as appropriate

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23: Prevention Using Prenatal Diagnosis and Preimplanation Genetic Diagnosis "We knew we were both carriers when we got married so there was always that risk. With my first baby I refused PND and he was born with thalassaemia. I don't think I could cope with more than one child with thalassaemia so I chose PND with my other pregnancies."

Aims To ensure that all couples at risk for having children with a thalassaemia disorder - including β thalassaemia major, β thalassaemia intermedia, haemoglobin E/β thalassaemia, α zero thalassaemia hydrops fetalis or severe haemoglobin H disease – are enabled to make informed choices concerning their reproductive options, through specialist genetic counselling. To support couples to have healthy families.

Standards  All couples at risk of having children with a thalassaemia disorder should be referred to specialist genetic counselling as soon as the risk is recognised.  Counselling is provided by a genetic specialist with specific experience in both prenatal diagnosis and preimplantation genetic diagnosis for haemoglobin disorders.  DNA analysis is provided for all at risk couples.  All at risk couples are informed of prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) as options to achieve a healthy family.  A couple at risk of having a child with a thalassaemia disorder should be offered PGD if the female partner is under 40 years of age at the time of treatment, and there is no living unaffected child from the current relationship.  If the woman has a thalassaemia disorder, her treating haematologist should be involved in the management plan prior to PGD.

Background Prenatal diagnosis Prenatal diagnosis (PND) using chorionic villus sampling (CVS) is available to all at risk couples from 11 weeks gestation onwards. PND, undertaken by experienced operators, carries a risk of miscarriage of 0.5% (Jauniaux and Petrou 2013). If a woman presents in later pregnancy, and the placenta is not accessible for CVS then amniocentesis may be carried out instead. DNA testing should be offered to both partners (ideally before any pregnancy) to identify the precise mutations they carry. The woman should be encouraged to self-refer for counselling for

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prenatal diagnosis as soon as a pregnancy is confirmed, so that CVS, if chosen, can be planned by the 11th week of pregnancy. If prenatal diagnosis shows an affected fetus, the woman should be offered termination of pregnancy. If this is her choice, termination should take place as a matter of urgency and preferably within five days of the woman receiving the result, so she has the option of an early surgical termination of pregnancy. If prenatal diagnosis shows an unaffected fetus, and the couple already have a child with thalassaemia, fetal HLA typing should also be performed. If the fetus and the affected child are HLA-compatible, cord blood cells should be collected at birth, and stored for possible transplant to the affected child in the future.

Preimplantation genetic diagnosis (PGD) PGD is the only way for an at risk couple to ensure a fetus is unaffected, while avoiding the risk of an invasive procedure and the risk of termination of pregnancy associated with conventional prenatal diagnosis. It may be acceptable to some couples who would not accept a termination of pregnancy on religious or other grounds. It allows the diagnosis of single gene disorders such as thalassaemia, or of chromosomal abnormalities, or HLA typing, in IVF embryos before they are transferred to the woman’s uterus. PGD is used by fertile or infertile couples at high risk of transmitting a genetic condition to their children, and there is now excellent evidence that it is safe and accurate. Ever since it was introduced in 1990 (Handyside et al. 1990; Verlinsky et al. 1990) the number of indications for PGD has increased steadily, as has the number of couples requesting PGD. It is estimated that over 16,000 children have now been born using PGD. However PGD is a long and complex process that combines in-vitro fertilisation (IVF) techniques with DNA testing. The pregnancy rate for a young woman is approximately is 29% (1 in 3) per embryo transfer with an average of 1.9 embryos transferred (Harper et al. 2012). Seven main steps are involved 1. The couple has a ‘genetic work up’ to determine the best method for embryo testing. 2. The woman undergoes controlled ovarian stimulation. This results in multi-follicular growth and suppression of ovulation. 3. Transvaginal egg collection. Approximately 36 hours before the egg collection, a ‘oneoff’ injection of hCG is given, when three or more follicles measure greater than 18mm. Under sedation the ovarian follicles are aspirated under transvaginal ultrasound control via a needle passed through the vaginal wall. Eggs are identified within the follicular aspirate. 4. A sperm sample is provided by the man. The eggs are fertilised using intra cytoplasmic sperm injection (ICSI), to prevent paternal contamination from excess sperm lodged in the zona pellucida (Harton et al. 2011). Only mature eggs can be injected by ICSI. 5. Eggs using polar body biopsy (rarely used) or more commonly embryos are biopsied at day 3 (blastomere biopsy) or at 5-6 days (trophectoderm biopsy) after fertilisation. The trophectoderm-biopsied embryos are cryopreserved to provide sufficient time for the genetic analysis. 6. Embryos that do not have a thalassaemia gene disorder are identified by DNA testing of the embryonic cells or polar body. 7. One or two unaffected embryos are transferred into the woman's uterus, either in the stimulated cycle or a subsequent cycle if embryos are frozen. Embryos can remain in storage for up to 10 years (HFEA). The chance of successful thaw is not affected by the duration of storage. Current HFEA guidelines allow transfer of a maximum of two embryos in women less than 40 years of age. A pregnancy test is carried out 14-16 days after embryo transfer. The likelihood of becoming pregnant is strongly linked to the age of the woman being treated. On average a woman aged 18-34 years of age is more likely to conceive than an older woman.

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Misdiagnosis after PGD is complex and difficult to identify: however there is agreement on an overall misdiagnosis rate of 0.14-0.27% after embryo transfer (Harper et al. 2012; De Rycke 2015). All women who become pregnant following PGD should be offered prenatal diagnosis by CVS. A cycle may need to be cancelled due to under-stimulation of the ovaries, or over-stimulation which may lead to ovarian hyperstimulation syndrome. On occasion, there may be no suitable embryos to transfer as some may not have fertilised, some may have not survived the biopsy procedure, or all embryos may be affected. Couples should avoid unprotected intercourse before the procedure and afterwards until the outcome of the procedure is known, to avoid the risk of a natural conception and the risk of an undiagnosed affected child. The treating haematologist should be involved in the management plan with the IVF team. If the woman has a thalassaemia disorder then the haematologist should review the suitability of the woman to undergo IVF treatment, including a review of the chelation regime, when iron chelation treatment and other medication should stop prior to the procedure, optimal transfusion therapy during treatment, a cardiology review, liver assessment and requirement for thromboprophylaxis during treatment.

Access to PGD PGD is available at several centres in the UK as a private service. At present PGD is available on the NHS only to couples who meet the criteria in Table 23.1. Such couples are entitled to receive three complete cycles. If couples choose to have PGD and fall within the criteria for PGD funding, or are prepared to pay privately, they should be referred for PGD.

Table 23.1: Access criteria for PGD on the National Health Service (NHS) Access criterion

Position for thalassaemia disorders

The couple is at risk of having a child with a serious genetic condition

Fulfilled

The risk of conceiving a pregnancy affected by a serious genetic condition should be 10% or more

Fulfilled

The couple have been referred to the PGD provider by an This requirement can cause delay because most clinical NHS clinical genetics service genetics services have limited experience with haemoglobin disorders, and so may refer patients back The couple have received genetic counselling from a to specialist haemoglobinopathy centres for counselling. clinical geneticist or a registered genetic counsellor The problem can be overcome by conducting joint clinics. The female partner is under 40 years of age at the time of treatment There is no living unaffected child from the current relationship The female partner has a body mass index (BMI) of more than 19 and less than 30 (but can be referred if she undertakes to lose weight) Both partners are non-smokers or undertake to stop smoking. The Human Fertilisation and Embryology Authority (HFEA) has licensed the indication for PGD

Yes

The test is included in the list of UKGTN approved tests, or suitable for inclusion

Licence is already in place for β thalassaemia, α thalassaemia and HbE/β thalassaemia

The couple must not be seeking PGD primarily because they are infertile

It is recognised that individuals with thalassaemia disorders may have to be treated for infertility

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It is possible to HLA-test unaffected embryos for compatibility with an existing affected child. However HLA testing is not included in the NHS criteria for PGD funding. It requires a specific application to NHS England, including evidence from the treating paediatric haematologist and the PGD centre. The process may be long-drawn-out and the application may not be successful.

Which couples should be referred for PGD? • At risk couples who wish to avoid the risk of having an affected child, but would not consider termination of an affected pregnancy. • Couples undergoing fertility assessments: couples who have been referred for IVF, or if the male partner has been referred for intra-cytoplasmic sperm injection (ICSI) may be suitable candidates for PGD. • Couples where one partner has a thalassaemia disorder (or has had a successful bone marrow transplant for thalassaemia) and the other is a healthy carrier. These couples are at 50% risk of having an affected child, in every pregnancy. • Couples at risk for more than one diagnosable genetic disorder. The chance of being at risk for two disorders is highest for couples who are close blood relatives. One in ten related couples at risk for thalassaemia is also at risk for another recessive disorder (for example, risk of thalassaemia plus risk of cystic fibrosis, phenylketonuria, maple syrup urine disease etc.). Such couples have a 43.75% risk of having a child with one disorder and a 6.25% risk of a child with two disorders. Counselling for related couples at risk for thalassaemia should include a basic family history designed to identify other possible genetic disorders in the extended family. If any potential disorder is identified the couple should be referred to a clinical genetic service for expert assessment of additional risk, including DNA testing when this is feasible. Both partners need to stop smoking as smoking has been shown to reduce the chances of conceiving. Cutting down on alcohol consumption to less than two units per week is recommended for men as excessive alcohol consumption can decrease sperm production and reduce motility. Women who hope to conceive should stop alcohol consumption.

Evidence base The European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium has been collecting data from international PGD centres since 1997. Yearly data collections are published from approximately 60 centres worldwide offering PGD. This data collection is an extremely valuable resource for monitoring accuracy, reliability, effectiveness and safety of PGD. For more technical details about PGD, readers are referred to Dahdouh EM et al. (2015) and Konstandinides et al. (2015). A summary of the first ten years of international data collection (1997-2007) showed that 17% of 27,000 cycles that reached oocyte retrieval were for risk of single gene disorders. The commonest indication was for haemoglobin disorders: 530 PGD cycles were for beta thalassaemia and sickle cell disorders, and 170 cycles for beta thalassaemia and HLA selection. The overall pregnancy rate was 23% per oocyte retrieval and 29% per embryo transfer (Harper et al. 2012). However the proportion of successful embryo diagnoses is rising (De Rycke et al. 2015), as is the proportion of successful pregnancies. The rate of referral for PGD is steadily increasing (Harper et al. 2012) and there is continuous improvement in available DNA diagnostic techniques (Lathi et al. 2012; Thornhill et al. 2015; Konstandinides et al. 2015) and there has been improved pregnancy rates of up to 63% of live birth per embryo transfer with trophectoderm biopsy, vitrification of blastocysts and transfer in a subsequent normal cycle (Lathi et al. 2012). The Human Fertilisation and Embryology Authority (HFEA) lists UK clinics and their success rates. In 2013, 18 clinics performed 533 cycles in 422 patients at risk for single gene or chromosomal disorders. These resulted in 137 births and 149 babies, giving an overall pregnancy rate per cycle started of 25.7%. (HFEA 2013). Currently the Centre of Reproductive and Genetic Health (CRGH) in London, where a significant number of PGD cases for single gene disorders are done, has the best success rates among UK 2016

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centres (see data on HFEA website www.hfea.gov.uk/preimplantation-genetic-diagnosis.html). For couples undergoing ICSI, there is a 61% clinical pregnancy rate per embryo transfer for women under 35 years of age, and 58% for women 35-37 years of age. However for PGD patients, the clinical pregnancy rate for single gene disorders is now reported to be 70% (personal communication CRGH). Approximately 5-10% of pregnancies achieved in this way will result in a spontaneous miscarriage.

Requirements  All at risk couples should be referred to a genetic specialist or genetic counsellor, with expertise in the genetic aspects of the haemoglobin disorders and prevention, to ensure the couple fully understand the risk of having an affected child and the benefits and limitations of available options for preimplantation genetic diagnosis and prenatal diagnosis.  DNA studies should be carried out on both partners.  The couple should be referred for PGD if they choose, and they fulfil the criteria in Table 23.1 or elect to pay for private treatment.  Couples opting for PND should be given the contact details of the PND centre so they can selfrefer as soon as a pregnancy is recognised, or the genetic counsellor should refer immediately on their behalf.  If the woman chooses to terminate an affected pregnancy following PND, this should be carried out as soon as possible and preferably within five days of the woman receiving the results.

Recommendations Couples seeking PGD should be advised that: • A cycle may need to be cancelled due to under-stimulation of the ovaries, or over-stimulation which may lead to ovarian hyperstimulation syndrome, or that there may be no suitable embryos to transfer as some may not have fertilised, some may have not survived the biopsy procedure, or all embryos may be affected. • They should avoid unprotected intercourse before the procedure and afterwards until the outcome of the procedure is known, to avoid the risk of an undiagnosed affected child. • All women who become pregnant following PGD should be offered prenatal diagnosis to confirm the results of PGD because the techniques used for PGD have technical limitations including the possibility of a misdiagnosis.

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Section D: NonTransfusionDependent Thalassaemias

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24: Management of NonTransfusion-Dependent Thalassaemias “People think thal intermedia is just a less severe type of thal major, but it has its own problems, especially as you get older.”

Introduction This section addresses issues covered by preceding chapters as they apply to NTDT. Where the same standards and key interventions apply, they are not repeated; where there are differences, these are highlighted. There have been developments in understanding the natural history and pathophysiology of NTDT since the last edition of the Standards (Musallam et al. 2011; Taher et al. 2010). Most of these derive from observations in the Middle East and some European centres, and may not be fully applicable to patients from other ethnic backgrounds, with different genotypes. For instance, cases of Haemoglobin E/β thalassaemia (EBT), a form of NTDT seen in people from Bangladesh and SE Asia, were not included in many of these studies.

Aims To maintain good health, normal growth and development, and a good quality of life during childhood, adolescence, and adulthood in people with NTDT, avoiding unnecessary treatment with regular transfusions in those with milder clinical features, but intervening with appropriate transfusion as needed. To monitor regularly and systematically for early signs of morbidity due to chronic anaemia, iron overload and other consequences of untransfused thalassaemia.

Standards  A comprehensive DNA diagnosis (β globin mutations, α globin genotype, Xmn1 C→T polymorphism) should be undertaken as soon as the diagnosis of thalassaemia has been established.  Parents, carers, and patients should be counselled at diagnosis, and as often as needed thereafter, about the likely course of the condition and therapeutic options available.  During the first 3-5 years of life, children with thalassaemia should be monitored carefully and systematically for evidence of thalassaemic features which may require regular transfusion therapy. Older children, adolescents and adults with a diagnosis of NTDT should continue to be monitored regularly, for consideration of indications for transfusion, and for iron loading, pulmonary hypertension, and extramedullary haematopoietic masses in particular.  Complications of NTDT should be identified at an early stage and treated promptly.

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Background Definition NTDT encompasses the spectrum of clinically significant thalassaemia syndromes which do not require regular transfusions in early childhood to sustain acceptable health, growth and development. The definition includes a broad range of phenotypes and genotypes, and can be subdivided into those who have never been transfused and those who require occasional transfusions. This has not been formally defined, but may be up to 6 transfusions per year (Taher et al. 2011; Weatherall 2012). The pathophysiology and severity of iron overload in these two groups will differ, and in general iron overload and the need for chelation is likely to be increased in the latter group.

Genetics NTDT can be the result of inheritance of milder β globin gene mutations, allowing sufficient β globin chain production for some adult haemoglobin production. Additional genetic factors, such as co-inheritance of α thalassaemia, or the inheritance of a genetic determinant of enhanced fetal haemoglobin production, can also alleviate the severity of the thalassaemia. An important effect of these additional factors is to reduce the intracellular damage due to free α chains within the developing erythroblast. The clinical phenotype can usually be predicted from knowledge of the β globin, α globin and Xmn1 polymorphism analysis (Table 24.1) but sometimes the clinical phenotype is not as predicted from genetic analysis. The α thalassaemia syndrome Haemoglobin H disease (HbH) has a relatively variable phenotype and is usually mild, although in a few cases may be severe enough to require regular transfusions.

Table 24.1: Genetic determinants of non-transfusion-dependent thalassaemia Homozygote (or compound heterozygote) for mild β-mutation (such as IVS1-6 T>C, Codon 9 C>T) Homozygote for Xmn1 polymorphism Homozygote for severe β mutation but persistence of Hb F due to: HPFH Other factors increasing HbF Co-inheritance of β thalassaemia (heterozygote) and a thalassaemia-like Hb variant (these may result in a major or intermedia phenotype)

Hb E/β thalassaemia Hb Lepore β thalassaemia

Co-inheritance of α thalassaemia mutations (homozygous α or heterozygous α0) with homozygous β thalassaemia resulting in decreased globin chain imbalance +

Co-inheritance of extra α gene(s) with heterozygous β thalassaemia resulting in increased globin chain imbalance Inheritance of a ‘dominant thalassaemia’ mutation (hyperunstable β globin variant)

Clinical phenotypes Moderate/severe This includes up to 10% of patients with homozygous β thalassaemia, the majority of those with EBT and a very small proportion of those with HbH. At the severe end are patients who can only just manage without transfusions, but who have severe anaemia, reduced exercise tolerance, mild to moderate bone changes, hypersplenism, poor growth during childhood, and a delay in pubertal development. They are likely to develop gall-stones, extramedullary haematopoietic masses, and osteoporosis and will gradually accumulate iron, particularly in the liver, due to increased gastro-intestinal iron absorption. The majority in this group end up requiring regular transfusions (Taher et al. 2015; Taher et al. 2014).

Mild This group includes a small proportion of patients with homozygous β thalassaemia (usually predictable from genotype), some patients with EBT, and the large majority of patients with HbH. It is important to identify this very mild group and to provide information tailored to their 2016

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condition. Long-term complications including pulmonary hypertension, hypersplenism, gall stones, endocrinopathies, osteoporosis, chronic ankle ulceration, thromboembolic disease and iron overload can occur, but usually not before the age of 30.

Specific clinical considerations Transfusion Considerations to be taken into account in deciding whether to start a child on regular transfusion include the following: • Episodes of acute anaemia may be related to intercurrent infection and are not necessarily an indication for long-term transfusion. • Parvovirus B19 and other viral or atypical infections are common causes of acute resolving anaemia. The haemoglobin level returns to baseline once the infection resolves. • It is important to remember that acute haemolysis may also be exacerbated by G6PDdeficiency, and that folate deficiency may occur; patients with NTDT should be prescribed folic acid supplements. • Transfusion initiated for delayed growth and pubertal development in NTDT should be reviewed once growth is complete. • Older patients may become increasingly symptomatic with anaemia and regular and transfusion programme may be indicated. • Since red cell allo-immunisation is common in NTDT with incidence varying between 4 – 37% (Taher et al. 2015), phenotype matched units for transfusion is mandatory.

Splenectomy Splenectomy should be considered for patients with: • hypersplenism resulting in clinically important leucopenia, thrombocytopenia, bleeding or symptomatic anaemia; • massive splenomegaly with clinical symptoms. Previously splenectomy was recommended in order to increase haemoglobin level and avoid regular transfusion. However, it is increasingly clear that splenectomy does not provide a permanent alternative to transfusion in these patients, and probably increases the risk of longterm complications such as thromboembolic disease and pulmonary hypertension. Avoidance of transfusion is no longer a standard indication for splenectomy in the UK, where blood is readily available and safe, and several options for iron chelation exist.

Managing iron overload Recent data has shown that iron overload complications are associated with considerable morbidity in patients with NTDT and that this is under recognised. The serum ferritin is unreliable in NTDT, and underestimates the degree of liver iron loading. Iron -related cardiomyopathy is rare in NTDT but endocrinopathies are encountered (Taher et al. 2014; Taher et al. 012). Patients should be offered liver iron monitoring by either T2* or R2 (Ferriscan) to assess the degree of iron burden.

Liver iron concentration (LIC) The relationship between LIC and total body iron which has been established in TM is not applicable to NTDT, and the mechanism of iron deposition differs. Therefore, LIC values in NTDT should be interpreted with caution. Liver iron increases by an average of 0.35 mg/g dw per year in NTDT patients. Some studies have shown an association between age and LI, but others have not been able to demonstrate this (Taher et al. 2012; Pakbaz et al. 2007; Taher et al. 2008; Origa et al. 2008).

Serum ferritin Although levels of SF correlate with LIC in NTDT, potentially toxic LIC levels are associated with lower SF levels than in TM, and the range of values of SF used to predict morbidity and mortality in TM may not be directly applicable NTDT. In one study, the authors found elevated LIC levels in

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patients with SF levels below 1000 μg/l, a level generally considered safe in TM (Taher et al. 2012; Pakbaz et al. 2007; Taher et al. 2008; Origa et al. 2008).

Myocardial iron In cross-sectional studies using myocardial T2* MRI, non-transfused or rarely transfused NTDT do not appear to have measurable cardiac iron loading. There is insufficient published data to assess the long-term risk of cardiac iron loading beyond the age of 40. Furthermore, for patients who switch to regular transfusions, there is a risk of cardiac iron accumulation as for TM (Taher et al. 2010; Taher et al. 2009).

Non-transferrin bound iron (NTBI) Detectable NTBI has been reported in one study, associated with the frequency of previous transfusions (12). This may relate to increased uptake and mobilisation of iron which is thought to relate to low hepcidin levels in NTDT. Thus, NTBI may be apparent before serum transferrin is fully saturated, in contrast to TM, where NTBI is detected when erythropoiesis is suppressed, hepcidin levels normal, and transferrin fully saturated. It is not yet clear how NTBI levels correlate with clinical outcomes in NTDT and whether NTBI levels can be used clinically to decide on initiation and adjustment of chelation therapy.

Iron chelation in NTDT There have been a number of small uncontrolled trials of chelation therapy with DFO (Cossu et al. 1981), and DFP (Olivieri et al. 1992; Rodrat et al. 2012; Limenta et al. 2011), which have demonstrated that these agents can chelate iron in NTDT patients with an acceptable short-term safety profile. An initial pilot trial (Voskaridou et al. 2010) and a more recent placebo controlled trial (Taher et al. 2013) have shown that DFX is safe, effective and acceptable for reducing LIC and SF at doses of 5, 10 and 20 mg/kg. The lower limit of LIC for inclusion was 5 mg/g/dw. There have been no studies which compare different levels of liver iron at which to start chelation therapy, and no studies which demonstrate a beneficial effect of chelation on morbidities in NTDT.

Pulmonary hypertension (PHT) PHT is prevalent in untransfused adults (30%), particularly those who have been splenectomised, and causes significant morbidity and mortality (Musallam et al. 2011; Taher et al.2010; Taher et al. 2011; Teawtrakul et al. 2014; Teawtrakul et al. 2015). Autopsy studies show pulmonary vascular occlusion with thrombus, presumably a result of hypercoagulability, increased platelet count and activation. Nitric oxide depletion through scavenging by free plasma haemoglobin may also play a role in promoting pulmonary vascular changes. Echocardiography is a useful screening test, particularly if done sequentially. If there is a suspicion of PHT on the basis of clinical symptoms and signs, and/or findings on echocardiography, referral should be made to a specialised unit for assessment and consideration of right heart catheterisation to confirm the diagnosis. Patients with PHT should be managed jointly with a national specialist PHT unit. Treatment options include hypertransfusion and hydroxyurea. Anticoagulant therapy may be beneficial in some cases. Decisions about specific therapy for PHT including sildenafil and endothelin antagonists should be guided by the PHT specialist centre.

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Extramedullary haematopoiesis Asymptomatic paravertebral masses are observed in 15% - 20% of patients. Symptoms can be subtle, for example a feeling of incomplete bowel emptying can indicate a pre-sacral mass, and spinal cord compression may be present in individuals who complain of minor symptoms of weakness or discomfort in a knee joint. A full neurological examination should be undertaken if there is any suspicion, with consideration of MR scanning of the spine. Masses causing spinal cord compression, root compression, or pressure symptoms in other anatomical sites require urgent management. The optimal treatment modality is not established but radiotherapy can induce rapid resolution of pressure effects. Good results, although generally slower in onset, have been described with hypertransfusion and hydroxycarbamide. Asymptomatic masses may require therapy depending on their position (e.g. if impinging on the spinal cord), but if not threatening vital structures, for example lying in the paravertebral gutters in the thorax, may simply be monitored.

Low bone mineral density (BMD) Low BMD is very common in NTDT. One cross sectional study found Z score 800μg/l) should prompt a repeat LIC assessment.  Myocardial T2* should be considered for assessment of myocardial iron loading in older patients and those who require more frequent transfusions (3-6 per year).  Iron chelation is recommended in older children and adults whose LIC is more than 5 mg/g/d.w.  DFX is recommended as first line chelation, with the goal of reducing LIC and maintaining within the range 3-7 mg/g d.w. The starting dose should be 10 mg/kg/day and dose adjusted within the range 5-20 mg/kg/day on the basis of monthly SF and periodic LIC. DFX should be discontinued when LIC 3 transfusions per year

5 yearly

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Appendices

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Appendix A: Summary Guide to Routine Investigations Establishing the diagnosis A diagnosis of thalassaemia should be anticipated from antenatal screening of the parents and established by prenatal diagnosis where requested. Otherwise, it may be suggested by the results of the newborn screening programme. Occasionally the diagnosis will not be made at these early stages, and the diagnosis is suggested by clinical presentation as the child becomes ill. Testing to confirm a diagnosis should include: • Full blood count and blood film examination • Haemoglobin analysis by electrophoresis, high performance liquid chromatography (HPLC) or equivalent •  and  globin genotyping, and Xmn1 C→T polymorphism • Family studies may be informative, if parental results are not available through antenatal screening.

Before a first transfusion Specialty

Investigations

Haematology

Serial Hb measurements G6PD screen + assay if low

Transfusion

Full red cell extended phenotype and genotype (C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis)

Biochemistry

LFT and baseline ferritin assay

Microbiology

Hepatitis B surface antigen Hepatitis C antibody HIV antibody

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Monitoring tests during iron chelation Desferrioxamine, DFO Ferritin

1-3 monthly

Deferiprone, DFO (or combination with DFO)

Deferasirox, DFX

1 -3 monthly

Monthly

Neutrophil count not required

Manufacturers recommend weekly during therapy

not required

Creatinine

not required

not required

Twice before start, then weekly during first month after initiation and change of dose. Thereafter monthly.

ALT

not required

not required

Twice before start, then 2 weekly for first month after initiation of therapy. Thereafter monthly.

Urinalysis

not required

not required

Twice before start, then weekly during first month after initiation and change of dose. Thereafter monthly.

Pure tone audiometry

6-12 monthly for combination Annually aged > 5 years DFO and DFP, not if used as Before starting therapy and annually single agent

Ophthalmology

6-12 monthly for combination Annually aged > 5 years DFO and DFP, not if used as Before starting therapy and annually single agent

Tissue iron levels should be monitored by MR techniques: For liver iron concentration – starting from age 7 – 10 or as soon as able to tolerate procedure without sedation, and then repeated at intervals depending on previous result: • Stable levels in the range 3 – 7 mg/g dw: 1 – 2 yearly • Levels > 7 mg/g dw: yearly • Levels falling rapidly or < 3 mg/g dw: 6 – 12 monthly. For cardiac iron levels – starting from age 7 – 10 or as soon as able to tolerate procedure without sedation, and then repeated at intervals depending on previous result: • Stable T2* > 20 milliseconds: two yearly • T2* 10-20 milliseconds: yearly • T2* < 10 milliseconds: 6 monthly Note: see also cardiovascular assessments, below.

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Growth, development and endocrine function Measurement

Frequency

Assessments of weight and height – sitting and standing 6 monthly from diagnosis until final adult height. Assessment of puberty, using Tanner staging

Yearly from age 10 years

Plain X ray of wrist to check for epiphyseal fusion

1-2 yearly from age 10 if concern about fall in height velocity or pubertal progression

Growth hormone stimulation test

If declining growth velocity from age 8

Oral glucose tolerance test

Yearly from puberty, or from age 10 years if family history of diabetes mellitus

Full annual diabetes review, including glycaemic control, cardiovascular risk factors, diabetic complications and Yearly if a diagnosis of diabetes is established sexual health Thyroid function test

Yearly from age 12, or if any suggestive symptoms of thyroid deficiency between times

Calcium, phosphate, alkaline phosphatase levels Parathyroid hormone level

6 monthly from age 12 If calcium level is low

Vitamin D level

At least every year from age 2

Morning cortisol level

Yearly from age 14

LH/FSH and oestradiol

If menstrual disturbance develops

Morning testosterone level

Yearly from age 14

LH/FSH and sex hormone binding globulin level

In men if morning testosterone level is low

Assessments for fitness for pregnancy. • Cardiology review including echocardiogram and T2* cardiac magnetic resonance scan • Glucose tolerance test to exclude diabetes • In known diabetic, fructosamine level, as indicator of glycaemic control, aiming at < 300 nmol/l • Thyroid function • Hepatitis B serology – ensure fully immune • Check up to date with other immunisations for example pneumococcal vaccine if spleen removed • Bone density by DXA scanning

Acute clinical presentations. Please refer to the full tables guiding diagnostic considerations in chapter 15: Acute Clinical Presentation .

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Cardiovascular assessments Uncomplicated, well chelated patient on stable therapy and without symptoms or abnormalities on previous testing Assessment


Comment

Clinical cardiology visit 7 – 10yr and examination

2 yr Annual 2 yr

If no symptoms/abnormalities Between risk ages 16 to 25 yr After age 25

ECG

As above

At each visit

7- 10yr

As above

At each visit

7- 10 yr

2 yr if > 20 ms on last assessment 1 yr if < 20 ms on last assessment

ECHO MRI

First visit

Poorly chelated patient, without heart failure or impaired LV function, AND patients recovered from an episode of acute heart failure AND those with impaired LV but no symptoms. Assessment


Clinical cardiology visit and Immediate, then 3 to 6 monthly examination ECG

At each visit

ECHO

6 monthly

MRI

6 monthly if T2* < 10 ms Yearly if T2* < 20 ms

Comment Dependent on severity of T2*; 3 monthly if 7 mg/g dw: yearly • Levels falling rapidly or 3 transfusions per year

5 yearly

Age 15

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Appendix B: Glossary ablation anomaly removal or destruction of tissue, usually by surgery but abnormality, usually of development in some cases by chemicals or medicines antenatal adherence literally “before birth”, meaning during pregnancy. the extent to which a person is able to take antibiotic medication exactly as prescribed medication to treat bacterial infections adrenal antibody small gland above the kidney which makes adrenaline protein the body’s immune system makes in response and other hormones to infection, to fight it off. Antibodies can be artificially aetiology provoked by immunisation/vaccination to try to cause prevent infection. Additionally, antibodies can form against other ‘unfamiliar’ proteins, for example after agranulocytosis blood transfusion, against some of the proteins on the absence or very low levels of granulocytes surface of the transfused red cells. (neutrophils), the white blood cells which fight off bacterial and fungal infections anticoagulation the prevention or hindering of coagulation of the aldosterone blood by an anticoagulant drug – includes Warfarin hormone which regulates salt balance, blood volume and heparin and newer ‘direct oral anticoagulant’ and blood pressure drugs (DOACs). albumin appendix/appendicitis/appendicectomy the major protein found in blood plasma small elongated projection at the beginning of the alkylating agents large bowel, which has no useful function in humans. drugs used for chemotherapy and sometimes used in It can become inflamed causing pain and fever conditioning for bone marrow transplantation (appendicitis) and may need to be removed alpha fetoprotein (appendicectomy) a chemical marker which can be measured in the blood. Its level is raised in, for example, liver cancer arteriosclerosis disease of the arterial blood vessels marked by and in some circumstances during pregnancy. thickening, hardening and loss of elasticity in the alpha globin aterial walls. one of the two proteins required to make adult type arthritis haemoglobin, the other being β globin. painful inflammation and swelling in joints amenorrhoea arthropathy absence of menstrual periods pain in the joints amniocentesis withdrawal of some of the amniotic fluid surrounding atrial fibrillation heart arrhythmia marked by very fast contractions of an unborn foetus to diagnose congenital the heart muscle of the atria, or smaller upper abnormalities chambers of the heart, causing an irregular, rapid anaemia heartbeat low blood level, specifically low level of haemoglobin (the red oxygen carrying pigment inside the red blood audiology clinical speciality of managing hearing. cells). audiometry angiotensin measurement of hearing hormone controlling arterial blood pressure 2016

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autonomic capillary not subject to voluntary control the smallest blood vessels in the circulatory system autosomal recessive carcinoma a gene which can be passed on to offspring by a the most common type of cancer or tumour. mother or a father, and which if inherited with a cardiac arrhythmia “normal” equivalent gene from the other parent, gives disturbance of the normal, regular heart rhythm. rise to no health problems (a healthy carrier). In order cardiac decompensation to develop a clinical condition, it needs to be inherited failure of the heart’s pumping mechanism to work from both parents. strongly enough. bacteraemia cardiologist infection in which bacterial organisms circulate in the doctor specialising in cardiology. blood cardiology bart’s hydrops fetalis clinical speciality of managing heart disorders. an unusual condition, which usually causes a late cardiomyopathy miscarriage or stillborn baby, caused by the foetus problem in the heart muscle, weakening the pumping inheriting no functioning alpha globin genes from action. either parent. Alpha globin is one of the two proteins cardiovascular required to make adult type haemoglobin, the other relating to the heart and blood vessels/circulation being β globin cartilaginous dysplasia beta globin abnormality of the developing cartilage, the smooth one of the two proteins required to make adult type material at bone ends causing joints to move smoothly haemoglobin, the other being alpha globin chemotaxis biliary tract movement by a cell or organism towards or away from the tube system leading from the liver into the small a chemical stimulus bowel, and carrying bile. This has the dual purpose of chelation aiding digestion and carrying waste products such as removal of excess iron from the body, using a specific bilirubin formed when haemoglobin is broken down in medication called a chelator. the liver. The gall bladder is a small storage pouch for chimerism/mixed chimerism bile between the liver and bowel. a situation following bone marrow transplant in which biopsy the patient’s own bone marrow remains functional a small sample of tissue removed for microscopic or alongside the donor bone marrow. other examination, in order to aid diagnosis or guide chlamydia treatment. a micro-organism sometimes found in the cervix, bisphosphonates which can cause fertility problems a group of drugs which help put calcium back into the cholangitis bones. inflammation of the bile ducts bone marrow transplant a major medical procedure in which the patient’s bone cholecystitis inflammation of the gall bladder. marrow, usually because of a condition such as cholecystectomy thalassaemia or leukaemia, is replaced by bone surgical removal of the gall bladder. marrow from a healthy donor of the same or very cholelithiasis closely matched tissue type. stones in the gall bladder or biliary tract. bone resorption a normal process in which bones are being continually chorionic villus sampling procedure, usually undertaken at 11 or 12 weeks of eaten away at their surface. It goes along with new pregnancy, to remove a small piece of the placenta in bone formation, and the result of the two is called order to test for a condition which may affect the fetus. bone remodelling cirrhosis bradycardia a liver disease which can be caused by a range of slow resting heart rate problems, in which the liver is scarred with areas of butyrate functioning liver tissue trapped between scar tissue a naturally occurring fatty acid chemical which has bands been shown to increase production of foetal or baby type haemoglobin in certain circumstances

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colic dysrhythmia spasms of pain caused when a hollow organ is disturbance in the heart’s normal, regular rhythm. blocked, for example, the bowel or tubes of the biliary echocardiography tract an ultrasound scan of the heart in which the creatinine movement of the heart muscle and heart valves can be a chemical waste product produced by muscle visualised. metabolism; levels in blood are used to measure electrocardiogram (ECG) kidney function as the kidneys clear it when they are a tracing representing the heart’s electrical action working properly electrophoresis ct scan a laboratory technique in which different proteins in computerised tomography imaging technique which solution are separated, by passing a weak electric interprets multiple X-ray images to visualise internal current through the solution. anatomy embolism cystic fibrosis obstruction of a blood vessel by a mass (usually a an autosomal recessive condition, in which the blood clot) affected individual has chronic cough, repeated lung endocrine infections and difficulty with digestion relating to hormones deferasirox endocrinologist an iron chelating drug which is active when taken by a medical specialist in conditions causing hormone mouth. Its original name was ICL670 and it is licensed disturbance under the name Exjade. endocrinopathy deferiprone a condition affecting the hormone producing glands an iron chelating drug which is active when taken by enzyme mouth. Its original name was L1, and it is licensed a protein chemical which speeds up metabolic under the name Ferriprox. processes in the cells of the body. The level of certain densitrometry (bone) enzymes can be measured and may give a guide to measurement of bone density or strength of the the condition of the organ producing them (for bones. example, liver enzymes). desferrioxamine epiphyseal fusion the first available iron chelating medication which is epiphyses are the ends of the growing bones. When a still the most commonly used. It is licensed under the person is reaching maturity, the epiphyses fuse or lock name Desferal. It is not active when taken by mouth. together with the main part of the bone in certain diabetes mellitus areas, after which no more growth can occur. a condition in which the body is unable to process erythroid carbohydrates and sugars properly. relating to red cell production diabetes Type 2 erythroid marrow hyperplasia a type of diabetes which is usually of later onset, and overgrowth of the bone marrow caused by increased which frequently responds to diet or tablets rather red cell production. than needing insulin. erythropoiesis diagnostic imaging the process of red cell formation. a general term for any sort of X-ray or scan used to aid erythropoietin diagnosis the hormone produced by the kidneys which drives red diaphysis cell production. the shaft part of a long bone fallopian tube disc disease the tube which connects the ovary to the body of the problems affecting the soft tissue discs which sit uterus or womb. between the spinal bones and aid spinal movement. ferritin diuretic a soluble transport form of iron, which can be a medication which increases the kidneys’ output of measured in the blood and used as an indication of salt and water, causing an increase in urine output. the total amount of iron in the body. dysplasia fetus (also spelt foetus) an abnormality of development the unborn baby.

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fludarabine a chemotherapy drug also used in conditioning regimens prior to stem cell transplant folic acid a vitamin of the B group which is required for red cell formation. It is found in green leafy vegetables and nuts. fracture breakage (of a bone). free radical unstable atom or molecule which is highly reactive and can cause cell damage fructosamine a protein used to assess long term glucose control in diabetes fulminant full-blown or obvious. G6PD deficiency low levels of a chemical called glucose 6 phosphate dehydrogenase, found in the red cells, which is used by the red cells to resist damage by certain chemicals. Deficiency is an inherited condition, usually causing few problems but which can lead to red cell breakdown, especially if a person takes certain medications which should therefore be avoided. gall bladder is a small storage pouch for bile, positioned on the biliary duct or tube between the liver and bowel gall stone a lump of hard material developing in the biliary system or gall bladder gene an inherited instruction which determines one or a number of functions which occur in the chemical machinery of the cell. The gene consists of a stretch of DNA containing unique coding sequence which is eventually translated into a protein. This sequence is copied as the cell divides genetic relating to one or more genes geneticist scientist or doctor who has a specialist interest in conditions caused by genetic problems genotype a particular type or combination of genetic changes genu valgum tendency to have “knock knees”. Gestation the period from conception to birth globin the protein parts of the haemoglobin molecule.

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glucose intolerance a mild form of inability of the body to handle glucose and sugars optimally, not as severe as diabetes mellitus. gonadal relating to the organs of reproduction; ovaries in women and testes in men. gonadotrophin hormones produced by the pituitary gland in the brain that stimulate the ovaries and testicles graft rejection a situation where, after a transplant (for example, of bone marrow), the immune system of the person receiving the transplant reacts against it and tends to destroy it. graft versus host disease (GVHD) a condition following a transplant in which the functioning immune cells in the transplanted tissue react against and damage tissues of the person receiving the transplant. gram negative/gram positive organism bacteria which either do (positive) or do not (negative) stain with a reagent called Gram’s stain, used by laboratories to differentiate organisms viewed under the microscope. growth hormone deficiency a shortage of a hormone produced by the pituitary gland which is chiefly responsible for controlling growth. haematocrit percentage of the blood which is taken up by the blood cells as opposed to the fluid plasma. haematology the clinical speciality relating to blood disorders. haematologist medical specialist managing blood disorders. haematopoiesis the process of blood cell formation, which usually takes place within the bone marrow. ‘Extra-medullary haematopoiesis’ describes the situation in which the tissue performing this function extends outside the bone margins haemochromatosis a condition where the body gradually loads up with too much iron. The term usually refers to the hereditary sort, where too much iron is absorbed from the diet, rather than to the condition resulting from repeated blood transfusions. haemodynamic relating to blood circulation

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haemoglobin HIV the red, oxygen-carrying pigment which circulates in the ‘human immunodeficiency virus’, which causes the red blood cells. From infancy onwards the majority AIDS. type is adult-type or Haemoglobin A, and it is the beta HLA (human leucocyte antigen) globin protein part of this which cannot be made describes a set of proteins on the white blood cells. adequately in thalassaemia major. Commonly referred to as “tissue type”. haemoglobin H disease homeostasis a condition resulting from inheritance of only one self-regulating biological processes which maintain functioning alpha globin gene, of the usual four. It is normal chemical levels, temperature etc in the body usually quite a mild anaemia with not many clinical homozygote problems. a person who inherits the same gene type from both haemoglobinopathy parents, for example, beta thalassaemia major (beta a general term which covers all the inherited medical thalassaemia gene from both parents) or haemoglobin conditions which are due to abnormal or underSS sickle cell anaemia (sickle cell gene from both produced haemoglobin proteins. parents). haemolysis hormone replacement therapy premature red cell breakdown usually used to describe oestrogen hormones given to haemolytic women after the menopause, but can also relate to resulting from premature red cell breakdown. the replacement of any hormone which is lacking because of underactivity of the endocrine glands. haploidentical stem cell transplant transplant from a “half matched” related donor, e.g. HPFH (hereditary persistence of fetal haemoglobin) mother or father continued production of fetal or baby type haemoglobin into adult life. This is an inherited hepatic feature. relating to the liver. hydroxyurea (also known as hydroxycarbomide) hepatitis a medication used for many years for bone marrow inflammation of the liver. over-activity syndromes, but more recently found to be hepatologist of use in sickle cell anaemia and to some extent in medical specialist in liver disorders. thalassaemia. hepatomegaly hyperdynamic liver enlargement. very active, quick, usually applied to blood circulation hepatosplenomegaly hyperglycaemia liver and spleen enlargement. elevated blood sugar. heptaocellular carcinoma hyperkinetic cancer of the liver cells. hyperactive, fast-paced or excessive movement Heterozygote an individual who inherits one type of a gene from one hyperplasia abnormal increase in volume of new normal tissue parent, and another type from the other. Relating to cells haemoglobin disorders it most usually describes hypersplenism inheritance of a normal gene from one parent together overactive spleen, often also enlarged, resulting in with a thalassaemic or sickle gene from the other - the lowered blood counts. healthy carrier state. hypertension high performance liquid chromatography (HPLC) high blood pressure. an automated, rapid and accurate way of separating different protein bands in a solution, for example, hypertransfusion different sub-types of haemoglobin from a blood a transfusion regimen when a person is transfused up sample. to even higher levels than normally needed to keep well, for a particular therapeutic purpose, for example histology before surgery or to reduce bone marrow growing the appearance of tissue examined under a outside the bone edges, as pre-transfusion microscope. haemoglobin levels of 110 – 120 g/l (rather than the histopathology usual 90 g/l) can suppress bone marrow activity and the clinical speciality of analysing tissue specimens for production of the person's own blood cells more abnormality. effectively. 2016

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hypocalcaemia left ventricular ejection fraction (LVEF) low calcium level in the blood. the percentage of blood present in the left ventricle that is effectively pumped forward at each heart beat hypogonadism to supply the peripheral circulation failure of the normal activities of the testes in men, or ovaries in women. lipids organic fats and fatty acids hypogonadotrophic hypogonadism hypogonadism resulting from underproduction of macrophage gonadotrophin hormones which are produced by a large white blood cell which ingests foreign small gland inside the brain, and which normally drive particles/bacteria ovarian/testicular function. malocclusion (dental) hypoparathyroidism the teeth do not meet properly when the jaws close underactivity of the parathyroid glands which control maxillofacial body calcium levels. relating to the jaws and face hypothalamus meningitis a small gland situated deep in the brain which, with inflammation, usually by infection, of the meninges or the pituitary gland adjacent to it, controls many of the brain coverings. hormone producing glands. menopause hypothyroidism the time, in women, at which the ovaries stop underactivity of the thyroid gland, which controls the producing eggs and the periods cease body’s activity levels. metabolism iatrogenic the body’s chemical processes or activities. symptoms induced unintentionally by medical monotherapy treatment single drug treatment. inotropic morbidity affecting muscle contraction, especially heart muscle, illness. making the heart pump more strongly mortality intermedia death. when relating to thalassaemia, describes the condition MRI (magnetic resonance imaging) in which, although a person inherits a thalassaemic a scanning technique which gives clear pictures and gene from both parents, he/she can make enough no exposure to X-rays haemoglobin to get along without always needing MUGA regular blood transfusions. ‘multigated acquisition’ scan, which uses injection of a intrauterine radio-isotope to show up the heart muscle and inside the uterus or womb. measure its function jaundice myeloma a symptom of liver disease in which the skin and a cancer of the antibody -producing cells within the whites of the eyes are discoloured yellow (due to bone marrow excess bile pigments in the blood) myocardial ketones relating to the muscular tissue of the heart acidic chemicals produced by the body when fat necrosis instead of glucose is burned for energy, which can tissue death happen in diabetes or starvation neonate Klebsiella newborn a gram-negative bacteria which can cause serious nephropathy infections kidney problem laparoscopy neutropenia a procedure for looking and/or operating inside the abnormally low level of neutrophils (white cells) in the abdomen through small, keyhole incisions. blood laparotomy obstetrics an operation to open up the abdomen, using ordinary the medical speciality of caring for pregnant women ‘open’ surgery and their unborn children, until after delivery. leukaemia cancer of white blood cells.

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oedema pathophysiology abnormal accumulation of fluid in body tissues, the study of structural and functional changes in tissue causing swelling and organs that lead to disease oesophagus pericarditis the gullet connecting the mouth and stomach, down inflammation of the fibrous sac which surrounds the which the food is swallowed. heart. oesophagoscopy perinatal a procedure to look down into the gullet. around the time of birth. ophthalmology peri-operative the clinical speciality of managing eye disease. around the time of an operation. orthopaedics perioral the clinical speciality of managing bone and joint around the mouth. problems, particularly by surgery. peripheral osteomalacia towards the edges, in medicine usually used to bone weakness, usually resulting from lack of vitamin describe towards the hands and feet. D or calcium phenotype osteonecrosis describes the structure or appearances resulting from destruction of bone tissue different gene makeup, or genotype. osteopenia phlebotomy a mild degree of bone thinning. blood removal. osteoporosis physiology A more severe degree of bone thinning which can the study of normal body processes. cause pain and increased risk of fracture. physiotherapy ovary the speciality of trying to improve joint and muscle the organ in females which produces eggs. function and mobility, often by massage, exercise etc. ovulation pituitary egg production a small gland deep inside the brain, which, with the hypothalamus which lies next to it, controls most of oximetry the body’s hormone producing glands. a method of determining the amount of oxygen in the blood pneumococcus a type of bacteria (also known as streptococcus paediatrics pneumoniae) which in most people causes tonsillitis, the clinical speciality of caring for illness in children but in people whose spleen is absent or not working palpitations can get into the bloodstream and cause very serious sensation of irregular, hard or rapid heartbeat infections. pamidronate a medication (one of the bisphosphonates) which can polydipsia excessive thirst and fluid intake help put calcium back into bones). polymorphism pancreas (literally “many forms”) usually describing the large gland behind the stomach which secretes insulin possibility of different forms which can occur at a and other hormones single gene site parathyroid the glands which control calcium levels in the blood polyuria excessive excretion of urine and bones, by producing parathyroid hormone portal hypertension parenchyma increased blood pressure in the circulation of the liver the essential/functional elements of an organ prenatal diagnosis pathogenic diagnosis on a baby before birth. causing illness. prognosis pathology outlook or expected outcome. the study of disease processes, and of diseased tissues prophylaxis or organs treatment given to try to prevent a problem, rather than waiting until it develops and then treating it.

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pulmonary sinusitis relating to the lungs inflammation, usually caused by infection, in the sinuses pulmonary hypertension increase of blood pressure in the blood vessels of the spermatogenesis lung formation of sperm by the testes R2/R2* spleen a magnetic property of tissues which increases with large organ lying under the lower ribs on the left, raised iron content and can be measured by magnetic which helps in fighting infection and removes old or resonance imaging (MRI) damaged cells from the blood radiology splenectomy the clinical speciality of interpreting X-rays and other removal of the spleen diagnostic images. splenomegaly radiotherapy enlarged spleen the clinical speciality of giving treatment with staphylococcus epidermidis radiation. a type of bacterium which can infect tubes or ‘lines’ renal put through the skin into the veins so that medication relating to the kidneys. can be administered through them retina steatohepatitis the membrane at the back of the eye which senses fatty liver light and sends messages to the brain, where they are stem cells interpreted into vision. the earliest, most primitive cells in the body which can retinopathy mature into almost any of the tissues disease or problem affecting the retina. stomatitis rheumatology inflammation of the mouth the clinical speciality of managing joint disease (with sub-clinical medicine, not surgery). not apparent as not causing symptoms, or signs on rickets examination a condition which arises when the bones are softened subcutaneous by lack of vitamin D or calcium (osteomalacia), and under the skin which can cause deformity in developing bones synergy/synergistic rubella working together virus infection more commonly known as ‘German T2/T2* measles’. a magnetic property of tissues which falls with sensorineural increased iron content usually used to describe a form of deafness due to teratogen damage to the auditory or hearing nerves. an agent that can disrupt the development of a fetus; sepsis i.e. which causes birth defects infection, usually bacterial. tetany septicaemia muscle spasm caused by low calcium level in the blood infection in the blood. thromboprophylaxis serum medication given to try to prevent blood clots forming the clear fluid remaining when blood has been in the blood vessels allowed to clot and the clot removed. thrombosis serology blood clot forming in the blood vessels testing of serum. thyroid sickle cell disorders the gland which produces thyroxine hormone, which a group of inherited conditions in which altered controls the body’s activity levels structure of haemoglobin can give rise to anaemia, transaminases sudden severe pain ‘crises’ and a range of other health liver enzymes problems transferrin sinuses a plasma protein that combines with and transports air spaces within the bones of the face iron

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UKCCSG United Kingdom Children’s Cancer Study Group ultrasound a type of scan using high frequency sound waves vaccination injection to provoke an immune response to an infection, and therefore protect against it varices enlarged vein containing blood at higher pressure than usual vascular to do with the blood vessels (intravascular - inside a blood vessel) vasodilatation widening of blood vessels due to relaxation of the muscle in the vessel walls, allowing a greater volume of blood to flow

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ventricles when relating to the heart, indicates the main pumping chambers vertebra(e) bone(s) in the back or spine paravertebral around the vertebral bones vertebral dysplasia abnormality in development of the vertebrae Yersinia (enterocolitica) bacterial organism which can cause infection in the bowel, giving severe pain and fever which can mimic appendicitis. It infects particularly people who have high iron levels and are on iron chelation.

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